System and method for a physiochemical scalpel to eliminate biologic tissue over-resection and induce tissue healing

ABSTRACT

Removal of damaged tissue itself can enable biosynthetic activity in vivo as an unburdened homeostatic or repair response. By removing a biologic and mechanical irritant, the lesion site can be altered to a more favorable perturbation-specific mechanotransductive environment supportive of differentiated gene expression. One aspect of one embodiment of the present invention provides an engineered irrigant that produces ion exchanges in tissues for example deliver of protons which interact with biology tissues.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/405,044, entitled “SYSTEM AND METHOD FOR A PHYSIOCHEMICAL SCALPEL TOELIMINATE BIOLOGIC TISSUE OVER-RESECTION AND INDUCE TISSUE HEALING”,filed on Feb. 24, 2012, which claims priority to and the benefit of U.S.Provisional Patent Application No. 61/446,463, entitled “PHYSIOCHEMICALSCALPEL TO ELIMINATE BIOLOGIC TISSUE OVER-RESECTION AND INDUCE TISSUEHEALING”, filed on Feb. 24, 2011, and U.S. Provisional PatentApplication No. 61/547,566, entitled “INVERSE MASS RATIO BATTERY AN INSITU ENERGY SOURCE GENERATED FROM MOTIVE PROTON DELIVERY GRADIENTS”,filed on Oct. 14, 2011, the specification and claims thereof areincorporated herein by reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

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INCORPORATION BY REFERENCE OF MATERIAL SUBMITTED ON A COMPACT DISC

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COPYRIGHTED MATERIAL

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BACKGROUND OF THE INVENTION

Diseased tissue resection at the tissue surface requires precisionbecause tissue surfaces display the shared cell-to-matrix feature ofstructural stratification. Volumetric or functional over-resectioncorrupts tissue elements, including intrinsic homeostatic and repairmechanisms, concentrated within the superficial layers at and aroundthese lesions. For many conditions, this imprecision significantlyprovokes disease progression by eliminating contiguous tissue phenotypesand expanding lesion size toward unsalvageability. The ability to resectdiseased tissue precisely, unencumbering contiguous healthy tissuefunction without iatrogenic impairment of its differentiated phenotype,is a beneficial prerequisite to mitigate the disease burden oftissue-surface based medical conditions. Rather than resectiontechniques based on imperfect visual-tactile cues designed to unencumbercontiguous healthy tissue function, selective targeting of diseasedtissue traits protects against the iatrogenic collateral damage ofover-resection which can further impair contiguous healthy tissue fromretaining and displaying differentiated phenotypes. Early interventionbecomes more than an effort to stabilize these lesions into a transientpalliative remission indifferent to resection margin accuracy; itbecomes a tissue rescue harnessing features unique to tissue surfaces.

Tissue surfaces display a superficial-level healing phenotype becausethis region is required to interact most intimately with repetitiveexternal tissue-specific stressors. Without these attributes, tissueintegrity would be rapidly lost to environmental perturbation. Diseasedtissue surfaces manifest as forces or processes overload the tissue'scapacity to maintain integrity. Untreated, this tissue burden canultimately lead to symptoms of disease progression. While thetopographic loss of water-structured surface barrier regimes such asstratified zones of structured fluid organized in a potentiometricmanner of charge separated areas and the collagen failure of backuplayered cleavage planes occur during physiologic loading, these lesionsare generally self-repaired by intrinsic tissue assembly mechanisms. Thefactors by which in vivo self-repair becomes insufficient are complexand tissue-specific. Lesions that remain reversible require targetedresection of the diseased tissue that serves as a biophysical irritantimpeding regional tissue organization and assembly. This irritantchanges the tissue-surface microenvironment, impeding reconstitution ofdamaged surface barrier regimes and altering chemo-mechano-transductivegene expression in contiguous tissue, progressively advancing reversiblelesions toward failed differentiated homeostatic resistance capacity andan unsalvageable state characterized by non-reversible phenotypicalterations.

Early surgical intervention may be viewed as a tissue rescue, allowingarticular cartilage to continue displaying biologic responsesappropriate to its function, rather than converting to a tissueultimately governed by the degenerative material property responses ofmatrix failure. Early intervention may positively impact the latechanges and reduce disease burden of damaged articular cartilage.

A goal of early surgical intervention for treatment of articularcartilage damage is to stabilize lesions as a means to decrease symptomsand disease progression. Lesion stabilization remains a necessaryprerequisite toward articular cartilage tissue preservation sinceremoving the irritant of damaged tissue and creating a residuallyhealthy lesion site remain required substrates for permitting orinducing effective in situ healing responses.

For articular cartilage lesion stabilization, thermal and plasmaradiofrequency ablation devices originally appeared to be moreefficacious than mechanical shavers by exhibiting a smaller time-zerocollateral injury footprint. However, because matrix corruption andchondrocyte depletion within contiguous healthy tissue occurcommensurate with, and often significantly expand following, volumetrictissue removal, this technology did not become widely adopted as it isunderstandable that such damage can impair or inhibit in situ healingresponses as well as contribute to disease progression by enlarginglesion size. Despite optimizing ablation device performance, thiscollateral tissue damage transgresses tissue zonal boundaries whereinthe depth of necrosis in non-targeted tissue remains larger than nativeSuperficial Zone thickness. Consequently, the functional properties andvital healing phenotype of the Superficial Zone is always effectivelyeliminated. These collateral wounds originate because ablationtechnology, like mechanical shavers, cannot distinguish between damagedand undamaged tissue.

Utilizing direct electrode-to-tissue interfaces known in the artindiscriminately deposits current into tissue which causes surface entrywounds and subsurface necrosis through resistive tissue heating andtissue electrolysis; and, because of its high water content, articularcartilage is inherently at risk for efficiently pooling electrothermalenergy to a detrimental level. Some have advocated manually positioningthe active electrode away from healthy tissue to target diseased tissue.However, this technique significantly increases the amount of currentrequired to overcome the effects that the fluid-flow and convectiveforces present during surgical application exert on exposed deviceelectrodes. Others have offered that intentional current-based damageserves as a barrier to additional current deposition withoutdemonstrating damage efficacy. Still others utilize current to createionizing electromagnetic radiation associated with high temperatureplasma formation, which has raised further concerns regarding iatrogenicchondrocyte DNA fragmentation and nuclear condensation. Both can induceapoptosis, cellular senescence, decreased progenitor cell populations,diminished cellular differentiation potential, and altered extracellularmatrix structure and production. Additional effects of ionizingelectromagnetic radiation on chondrocyte behavior important for in situhealing responses remain a cause for concern.

The disturbance of surface-confined nanoscale assemblies in biologictissue brought about by nonnative interfacial environments duringtherapeutic intervention has received very little attention despite thesignificant role these assemblies play in maintaining tissue integrityagainst perturbation and pathologic solutes. While much has been writtenabout the interfacial nuances of tissue surfaces for over 125 years, theemergence of tissue rescue surgical procedures has generated a renewedinterest in surface-confined assemblies because these assemblies areenrolled to produce a healthy lesion site devoid of damaged tissue as ameans to unencumber innate and facilitative wound healing. Althoughbecoming increasingly more delineated in various tissue types,surface-confined assemblies remain complex and difficult to study, evenwithout imposing iatrogenic disturbances and non-equilibria treatmentconditions. Treatment venues that utilize endoscopic surgical accessprocedures to care for normally juxtaposed tissue surfaces necessarilyinvolve ambient media replacement and mechanical loading alterations,both of which disturb surface-confined assembly behavior despiteattempts to simulate in vivo conditions.

Endoscopic replacement media such as saline solutions were originallyintended to aid surgical visualization as native media do not displayeither consistent or suitable optical properties. Commensurate with thiseffort were attempts to limit detrimental effects upon interstitialmatrices and resident cells, followed by the consideration of medicaldevice performance within replacement media, both without significantdeference to surface-confined assembly effects or their reversibility(damaged tissue removal was an obvious entry-level procedural advanceonce endoscopic access and visualization was made possible. Forarticular cartilage, early efforts like powered mechanical shavers andelectrosurgical (thermal or plasma) ablation devices were based onimperfect visual-tactile cues rather than upon tissue traits that relatethe practitioner's ability to distinguish diseased tissue from normal ascorrelated to conditions that contribute to disease burden. Tissuerescue treatments are designed to unencumber contiguous healthy tissuefunction by selectively targeting diseased tissue traits to protectagainst the iatrogenic collateral).

Media replacement eliminates native fluid lubricants required toaccommodate physiologic movement between normally juxtaposed tissuesurfaces; consequently, interfacial behaviors associated withhydrodynamic fluid film dissolution-depletion occur so that surfaceasperities are no longer contained within the thickness of native fluidlubricant pools. Such native fluid film starvation is induced by thelower media viscosity associated with optical improvement and themechanical unloading that occurs by eliminating the normal contactbetween tissue surfaces. Because pressure build up in native viscouslubricants is inhibited during endoscopy, interruption of otherinterfacial regimes like squeeze film, interstitial biphasic,mixed-mode, or versions of elastohydrodynamic fluid film mechanisms caninevitably occur (replacement media pressurization within a constrainedendoscopic cavity can produce significant hydrostatic forces; and incertain settings, residual lubricant entrapment may occur. Further, therole of hydrodynamic fluid film regimes during endoscopy for poroustissue surfaces like articular cartilage remains to be fully clarified,including the effects porosity may exert upon wettability). Theseconditions favor the expression of boundary lubrication regimes whereatloading is carried by the surface asperities in a contact area ratherthan by a fluid film lubricant and at which surface chemistry dominatesworking properties.

Because the differential mechanical load that tissue surfaces experienceduring endoscopy is primarily due to surgical device contact, thissituation is ideally suited for the treatment of abnormal surfaceasperities as relative to boundary conditions. Conversely, thedisturbances provoked by fluid film starvation and absent hydrodynamicpressure regimes during endoscopy that express boundary conditionsconstitutes a tissue vulnerability that has been largely unrecognized asan etiologic factor associated with iatrogenic damage that furtherimpairs wound healing, expands lesion size, and contributes to diseaseburden.

Partial-thickness damaged tissue surfaces at locations requiringrelative motion characteristically exhibit abnormal surface asperitiesand the related absence of surface-confined assemblies associated withboundary lubrication regimes, features that serve as an effectivenanoscale trait-targeting substrate for tissue rescue procedures whichmimic biologic wound healing behaviors.

Note that the following discussion refers to a number of publications byauthor(s) and year of publication, and that due to recent publicationdates certain publications are not to be considered as prior artvis-a-vis embodiments of the present invention. Discussion of suchpublications herein is given for more complete background and is not tobe construed as an admission that such publications are prior art forpatentability determination purposes.

BRIEF SUMMARY OF THE INVENTION

One embodiment of the present invention is a method for treatingtargeted tissue comprising localizing an alternating current circuitdevice tip in a saline solution containing electroactive species inwhich targeted tissue of a host is found and deploying current to thealternating current circuit device tip located in close proximity to thetargeted tissue which device tip inhibits electrode-to-tissue contactbut permits a shielded reaction zone for the saline solution to reactwith device electrodes of the alternating current circuit device. Theelectrons move between device electrodes utilizing electron donor andacceptor carriers within the saline solution. A non-ionizingelectromagnetic field quanta is produced near the targeted tissue whenthe device tip is placed next to the targeted tissue and producingelectron donor and acceptor carriers associated with charged specieintermediaries formed above baseline dissociation rates of the salinesolution. The charged specie intermediaries are moved toward thetargeted tissue surface using redox magnetohydrodynamic propulsion. Aneffect upon the targeted tissue or the saline solution is induced thatis therapeutic for treating the targeted tissue.

In one embodiment, the effect is produced by inducing gene expressionwith energy that is not injury inducing to the targeted tissue. Inanother embodiment, the effect is produced by inducing superficialextracellular matrix volume contraction. In a further embodiment, theeffect is directing charged species intermediaries toward the targettissue. In yet another embodiment, the effect is precision resection ofthe targeted tissue. In a further embodiment, the precision resection ofthe targeted tissue is produced by denaturing exposed proteoglycanaggregates of damaged articular cartilage of the targeted tissue usingthe charged specie intermediaries in the saline solution having aninduced pH below an isoelectric point of targeted tissue. In yet anotherembodiment, the exposed proteoglycan is chondroitin sulfate proteoglycanthat resides as aggregates within the inter-territorial matrix atarticular surfaces. In yet another embodiment, the charged specieintermediaries created in the saline solution comprise protons.

In yet another embodiment the effect is stirring of the saline solution.For example, the stirring is microfluidic mixing of the saline solution.In yet another embodiment the effect is delivery of a pharmaceuticalagent to the target tissue. In yet another embodiment, the effect isextracellular matrix modification. In yet another embodiment, the effectis to upregulate chondrocyte proliferation. Still another embodiment,the effect is gene transcription initiation.

For example, the activated gene is indicative of differentiatedchondrocyte function. Further, the gene may be selected from Versican,COL2A1 and HSPA1A. In yet another embodiment, the chondrocyte is asurface chondrocyte from the target tissue. In yet another embodiment,moving the charged specie intermediaries toward the targeted tissuesurface is directionalized with a plenum. For example, the plenum hasopenings through which the charged specie within the saline solution arethrust.

One aspect of one embodiment of the present invention provides for atechnology that creates protons through electron acceleration.

Another aspect of another embodiment of the present invention provides atechnology that allows for the sequestration of protons to be deliveredto tissues.

Another aspect of one embodiment of the present invention provides for atechnology that delivers protons within an engineered irrigant forexample, the engineered irrigant is both a proton reservoir and deliveryvehicle.

Another aspect of one embodiment of the present invention provides anengineered irrigant that produces ion exchanges in tissues for exampledeliver of protons which interact with biologic tissues, includingspecific ion flows both into and out of said tissues.

Another aspect of one embodiment of the present invention provides for asystem that accelerates electrons that are close to the tissue to betreated and another aspect of an embodiment of the present inventiondrives creation of engineered irrigants and also stimulates geneexpression at safe thresholds by way of non-ionizing electromagneticfields. For example, using a high charge/mass ratio (like electrons, butcould be any other such high charge/mass ratio elements) enables the useof low energy requirements, increasing safety. This produces usefulirrigants having properties sufficient to modify diseased tissue as wellas safe stimulation of appropriate ion-targeted gene expression.

Another aspect of one embodiment of the patent invention provides forusing normal tissue assembly and repair mechanism, like homeostaticmechanisms, through gene expression, for targeting thresholdresponsiveness mechanisms at a safe level just above micro-environmentalnoise. A system and method of one embodiment of the present inventiontakes advantage of the normal tissue mechanisms which are universal atthis safe responsiveness level through electromagnetic fields. Anotheraspect of the embodiment of the present invention provides for utilizingnon-ionizing electromagnetic energy which is not detrimental to cells.It is known that too much electromagnetic energy, like ionizingelectromagnetic energy of plasma systems, is detrimental to cells.Non-ionizing electromagnetic energy uses safe forces to effect geneexpression. The effects at low threshold responsiveness levelscharacterize normal homeostatic and tissue repair/assembly mechanisms.

Tissue rescue medical device systems, such as a medical device sometimesreferred to herein as a physiochemical scalpel, deploy alternatingcurrent redox magnetohydrodynamics within media replacement solutions toproduce protonating engineered irrigants designed to disaggregateexposed damaged interstitial matrices through molecular cleavage planesnot protected from that irrigant by surface confined assemblies. Thistargeted molecular disaggregation prepares damaged tissue for mechanicalremoval by surgically blunt shear forces produced by the device edge tocreate a healthy lesion site devoid of damaged tissue. Because boundaryconditions display a kinetic friction coefficient that is invariantrelative to factors that influence formation of a fluid film, such assliding velocity and axial load, the mechanical implement design forarticular cartilage limits its function to low contact speed andpressure loading to yield a kinetic friction coefficient safe forexposed boundary lubrication regimes. Since increased surface asperitiessuppress the formation of surface-confined assemblies by decreasinginterstitial matrix surface hydrophobicity, a condition that impairswound healing behaviors, re-establishing surfaces devoid of damagedtissue decreases surface roughness so that surface hydrophobicity isincreased to a more normal level (i.e. for articular cartilage, acontact angle approximating 105°) supportive of and associated with thecapacity to build and maintain surface-confined assemblies.

The trait-targeting dynamics during saline solution media replacementtreatment conditions between surface-confined nanoscale assemblies andalternating current redox magnetohydrodynamic tissue rescue proceduresas deployed for commonly encountered articular cartilage lesionsexhibiting increased surface asperities are discussed herein. As eachcreates and maintains an electrochemical voltage potential duringtreatment, tissue rescue is conceptualized as a biophysical batterycircuit that deploys capacitive balancing as a trait-targetingmechanism.

Tissue surfaces display a complex tribochemical interfacial system thatintegrates phase-state transitions between ambient media anddifferentiated interstitial matrices. Tissue surface-confined assembliesare germ cell independent systems rooted in a foundation ofself-assembling amphiphilic bioaggregates which emerge in situ to managetissue boundaries intrinsic to interfacial venues at which juxtaposedtissue surfaces reside. This system enables solubilization of solidtissue surfaces by transforming the hydrophobic surface of normalinterstitial tissue matrices toward a hydrophilic character. To mitigatethe high surface hydrophobicity of articular cartilage interstitialmatrices (due to very low cell-to-matrix ratios) and their rheologicchemomechanical loading requirements, these assemblies are considered toconsist of multiple oligolamellar hydrophilic bimolecular layers rangingbetween 6-10 nm each and conceptualized as a large three-dimensionalreverse micelle approximating 450 nm in thickness. These layers absorband hold water within their charged core in the manner of hydrophiliclamina with a strong laterally bonded network exhibiting both lipidmobility and viscous resistance. The amphiphilic components areintegrated onto solid-liquid surfaces as surfactants in order to modifythe interfacial wetting behavior and free energy of hydrophobicinterstitial matrices, allowing boundary water to spread into a surfacebiofilm state rendering the surface more hydrophilic. As the watercontent of this layer fluctuates during perturbation, amphiphiliccomponents migrate to reduce surface tension and avoid hydrophobicadhesion. Surface-confined assemblies function to protect underlyinginterstitial matrices from physiochemical perturbation and like othersurfactants are often non-uniform in thickness, discontinuous, or candeposit in an island form dictated by surface geometry and interfacialenergy conditions. Because they have been shown to replenish byself-assembly mechanisms through surface loading at healthy tissuematrix sites or through native lubricant component delivery,surface-confined assembly mechanisms suggest a tissue homeostatic andrepair role that is related to their stability and durability as evidentin other tissue types. By serving as an occasional sacrificial layerthat is subsequently reconstituted as a means to help mitigate certainperturbation events, the ability to restore tissue surface propertiesafter removing the bioburden of damage tissue that suppressessurface-confined assembly formation and maintenance remains an importantwound healing approach.

Because pH (consider the robust charge barrier of the gastric mucosawhich exhibits similar surface-confined assembly behavior. Because pH isa useful in situ measure of electrochemical voltage potential, it can bemonitored by practitioners in order to titrate the delivery of proticsolvents during treatment) can affect the wettability, frictionalcoefficient, swelling, contact angle hysteresis, and interfacial energyassociated with surface-confined assembly behavior, intrinsicamphiprotic properties allow active acid-base equilibria maintenance andstabilization of ambient charged species. In so doing, surface-confinedassemblies function as a charge barrier that can modulate osmotic driveenergy and interstitial biphasic fluid movement during perturbation,ultimately serving as a link between tribological and mechanical regimesduring physiologic conditions. This charge barrier, because of itsamphiprotic properties, has been shown to be protective of underlyinginterstitial matrices during the physiochemical loading, such as ambientprotonation potentials, delivered by tissue rescue surgical procedures.In these settings when polar replacement media like saline solutions areutilized to express boundary conditions so as to delineate abnormalsurface asperities, surface-confined assemblies induce formation of anadditional longer-range charge barrier mechanism with energy storageproperties. As an attribute of water residing adjacent to hydrophilicbiosurfaces, an ordered-water molecular zone contiguous tosurface-confined assemblies forms within which thermal and densitygradients do not blend freely. This zone forms rapidly to a thickness of100-300 μm (even with the mechanical turbulence of vigorous stirring,such as that which occurs during endoscopy, this zone is not eliminatedbut has been shown to decrease in size), excludes solutes like salts,and is mechanically less mobile due to its crystalline-likearchitecture. This zone demonstrates electrochemical voltage potentialsbetween 100-200 mV such that the zone is negatively charged and balancedby a region of increased proton concentration within the contiguous bulkwater solution. This charge separation proton gradient is a non-thermalprocess that occurs by absorbing incident interfacial energy to augmentthe natural water dissociation processes. Because surface-confinedassemblies create a hydrophilic surface upon which this proton gradientveneer is formed, this zone supplies a source of stored interfacialenergy as a protonation potential during saline media replacement.

The technique of alternating current redox magnetohydrodynamics involvespositioning localized alternating current circuits in saline solutionscontaining electroactive species to move electrons between deviceelectrodes utilizing electron donor and acceptor carriers within hostmedia replacement fluid. This electron transport produces fuel cell likereversible redox reaction pairs associated with charged specieintermediaries formed above baseline solution dissociation rates uponwhich the attendant alternating current non-ionizing electromagneticfield quanta influence the reaction dynamics. These influences includecharged fluid acceleration that create magnetohydrodynamic propulsivethrust currents adapted for medical therapeutics as irrigants. These“irrigants within water” are comprised of regional structure alteredmolecular water exhibiting differential charged specie separation thatresults in a sequestered energy source contained within the irrigantthat is useful for surgical work.

Alternating current electron movement produces a repetitive molecularenergy conversion loop fuel cell in saline solutions involving saltbridge catalyzed splitting and reconstitution of the water molecule. Thethermochemical redox reaction pair can be represented as

$\begin{matrix}{{{\alpha H}_{2}O_{(l)}} + {\beta\;{{XCL}\overset{energy}{\longleftrightarrow}\left( {\alpha - \beta} \right)}H_{2{(g)}}} + {\frac{\;\left( {\alpha - \beta} \right)}{2}O_{2{(g)}}} + {\beta HCl}_{({aq})} + {\beta\;{X{OH}}_{({aq})}}} & (1) \\{{\left( {\gamma - \delta} \right)H_{2{(g)}}} + {\frac{\left( {\gamma - \delta} \right)}{2}O_{2{(g)}}} + {\delta HCl}_{({aq})} + {\delta\;{{X{OH}}_{({aq})}\overset{energy}{\longleftrightarrow}{\gamma H}_{2}}O_{(l)}} + {\delta\;{X{Cl}}_{(s)}} + \Delta} & (2)\end{matrix}$with the variables α, β, γ, and δ as the molar quantities that satisfythe oxidation reduction requirements for the overall reaction set and Δas the available heat and/or electrical energy. Attendant non-ionizingelectromagnetic field quanta influence this redox reaction pair to movereactant and product charged species formed above baseline solutiondissociation rates away from the device electrodes and directionalizedby a plenum. As regional proton concentration differentials increaseabove normal solution dissociation rates due to the magnetohydrodynamicpumping mechanism, an electrochemical proton gradient develops from theresultant charge separation, creating an irrigant with energy storageproperties similar to that created by surface-confined assemblies duringsaline media replacement. This energy source is maintained during deviceactivation and delivered to tissue surfaces as a protonation potentialbelow the isoelectric point of exposed damage interstitial matrices. Theprotonation potential is delivered in the form of a protic solvent thatbalances proton delivery with sensible thermal contributions typical ofacute wound healing exudates. In so doing, the irrigant battery energyis consumed by the exposed negative charge density of damagedinterstitial matrices leading to molecular disaggregation useful foreliminating damaged interstitial matrix tissue.

Proton gradients are a common biologic mechanism utilized to generateelectrochemical potential in order to convert and store energy.Regardless of their generation mechanism, by depicting proton gradientsas electrochemical cells, their electrical polarity can be representedas a unidirectional flow of electric charge suitable for direct currentmodeling. For example, biologic membrane-based proton gradients such asin mitochondria and chloroplasts can be depicted as − ∥|+ because thesegradients require a physical membrane structure to maintain chargeseparation after charge movement. Likewise, ∥ − + can represent a protongradient that forms adjacent to hydrophilic tissue surfaces such as thatgenerated by surface-confined assemblies during saline mediareplacement; and, − + can represent protonating irrigant gradients thatform within solutions without physical structures to maintain chargeseparation such as those generated by alternating current redoxmagnetohydrodynamics. In each instance, and although generated bydifferent mechanisms, these proton gradients serve as energy conversionsystems generated from electron transport between charge carriers tocreate protonation potentials. Consequently, each proton gradientelectrochemical cell is capable of direct current discharge of itsprotonation potential which can be represented in a battery circuit.

Because surface-confined assemblies form and maintain a proton gradientveneer when confronted with saline solution media replacement, andbecause boundary conditions are dominated by chemistry, alternatingcurrent redox magnetohydrodynamics was chosen for tissue rescue becausea similar proton gradient can be design formulated within the samesaline solution and delivered in situ as a trait targeting mechanism forareas of abnormal surface asperities associated with absentsurface-confined assemblies. Accordingly, trait-targeting energy can bemodeled as a direct current supercircuit represented by instantaneousvoltage energy transfers using the water molecule as an energytransducer. During tissue rescue, a proton gradient is formed that isdelivered to tissue surfaces, much like a portable battery, anddischarged as a protonation potential. Because the intermolecularhydrogen bond stretching frequencies of water demonstrate a proton basedfemto- to pico-second oscillation period, electron movements associatedwith alternating current polarity changes are less rapid so that waterprotons in the irrigant experience direct current forces (10¹²⁻¹⁵ Hzoscillation rate versus 10⁵⁻⁶ Hz circuit frequencies) during deviceactivation. Accordingly, irrigant batteries generated through motiveproton delivery gradients can be reduced to a direct current energystorage model capable of direct current discharge during contact with aspecific therapeutic target. Viewed historically, these intramoleculardynamics are analogous to a full-wave bridge electrolytic rectifier thatconverts an alternating current into a direct current except that redoxmagnetohydrodynamics produce a steady direct current electrochemicalvoltage potential from the rectified alternating current supply withoutusing a smoothing reservoir capacitor, capacitor-input filter, orvoltage regulator. During tissue rescue, the irrigant battery interactswith the tissue battery generated by surface-confined assemblies.

Normal tissue surface-confined assemblies create a hydrophilic substrateupon which a proton gradient veneer forms during saline solution mediareplacement. In this setting, an electrochemical circuit can beconceptualized as a direct current model of retained voltage potentialwith intact surface-confined assemblies serving as an insulatorsubstrate while the electrochemical gradient battery is charged byproton veneer formation mechanisms described above. Viewed in toto for aspecific surface-confined assembly geographic island with distinctmargins, a single continuous electrochemical cell can be conceptualizedas participating in a battery circuit and which retains a protonationpotential capable of discharge.

Because damaged tissue surfaces lack surface-confined assemblies andtherefore the formation of a proton gradient veneer, the exposedinterstitial matrix constitutes an abnormal hydrophobic region thatpresents its negative charge density to the treatment venue. Thisexposed negative charge density separates surface-confined assemblyislands through edge contact angle hysteresis with the damaged tissuesurfaces acting as an electrical ground. This ground leads to dischargeof adjacent tissue surface electrochemical cells as a protonating forceupon the negatively charged exposed tissue. This protonation potentialdischarge facilitates molecular disaggregation of damaged interstitialmatrices that already exhibit deteriorating surface-layered shearproperties of collagen fibril disruption and orientation changes, weakcollagen-to-proteoglycan bonds, proteoglycan and lipid depletion,aberrant water content, and decreased fixed charge density. Thisdisaggregation leads to a decrease in surface roughness that can lead toan increase in surface hydrophobicity toward a level capable of buildingand maintaining surface-confined assemblies necessary to facilitateincreased wettability, more normal chemomechanotransductive environmentsfor subadjacent tissue, and unburdened tissue homeostatic and repairmechanisms. This biopolymer disaggregation process mimics the briningeffects on damaged tissue of acute wound healing exudates.

At damaged tissue sites that exhibit a level of surface roughness whichcannot be disaggregated by the protonating discharge of adjacentsurface-confined assembly batteries alone during saline mediareplacement, tissue rescue procedures deliver an engineered irrigantprotonation potential that is capacitance balanced and with reversepolarity to that generated by surface-confined assemblies at normaltissue surfaces. The technique of capacitance balancing between theirrigant and tissue surface batteries is used so that varied capacitancebetween the two energy sources does not lead to significant discharge ofeither during treatment. By designing the irrigant battery with acapacity similar to the tissue surface battery, the reverse polaritydelivery is a safe targeting force because the engineered irrigant isvery portable within saline media replacement venues. Themagnetohydrodynamic propulsive force easily interrupts the interfacialdischarge of adjacent tissue surface protonation potentials andconcentrates a larger protonation potential at the exposed negativecharge density of the damaged interstitial matrices. This therapeuticprocess mimics the protic solvent generated by enhanced azurophilicdegranulation of polymorphonuclear neutrophil granulocytes during theearly phases of acute wound healing.

At sites where normally juxtaposed tissue surfaces require relativemotion, surface-confined nanoscale assemblies form in situ as functionalintegrators to manage the hydrophobic interfacial character anddifferentiated behavior of interstitial matrices. Once surface areasbecome damaged and exhibit abnormal asperities exceeding the capacity ofintrinsic homeostatic and repair mechanisms, surface hydrophobicitydecreases to a state upon which surface-confined assemblies cannot formor be maintained; a condition of interfacial dysfunction leading toaltered chemomechanotransductive environments for and provocation towardfurther pathologic phenotypic shifts in subadjacent tissue. Thebioburden that such damaged tissue represents is related to itsclearance potential; and, in settings of limited or acquired clearancedeficiency, wound bed preparation remains an important therapeuticendeavor. For this reason, trait-targeting interventions have beendesigned to afford practitioners the ability to create an healthy woundbed when intrinsic homeostatic and repair capacities may be overwhelmed.By mimicking the important mammalian wound healing behavior ofdistinguishing between normal and damaged tissue surfaces based upon thepresence or absence of surface-confined assemblies, the removal ofdamaged tissue associated with abnormal surface asperities decreasessurface roughness so that surface hydrophobicity can be increased tomore normal levels, producing conditions favorable to surface-confinedassembly nucleation, reformation, growth, and maintained lesion sitecoverage. By creating a healthy wound bed unencumbered by damagedtissue, the re-establishment of interfacial regimes upon return tonative environments post-treatment can restore conditions supportive ofdifferentiated function, including intrinsic homeostatic and repaircapacities, in subadjacent tissue.

The bioburden clearance potential for many damaged interstitial matrixsurfaces is augmented by the formation of acute wound healing exudateswhen intrinsic homeostatic and repair capacities are not adequate. Theseexudates precondition damaged tissue toward a state amenable for removalby mechanisms like phagocytosis. This preconditioning is brought aboutby protic solvents, such as those generated through azurophilicdegranulation of polymorphonuclear granulocytes during the acute phasesof wound healing, that are primarily responsible for biopolymerdisaggregation of damaged tissue present in a wound bed. Because therheologic requirements of normally juxtaposed tissue surfaces can createchallenges for establishing acute wound healing exudates andlocalization of associated cellular complements, this clearancepotential limitation above intrinsic homeostatic and repair mechanismshas been advanced as one reason why some differentiated tissue surfaceshave been linked with a reputation for poor healing capacity.Alternating current redox magnetohydrodynamic technology has beenadapted for surgical applications to address this clearance deficiencyby imitating the protic solvent component of acute wound healingexudates to produce biopolymer disaggregation of exposed damaged tissuenot protected by surface-confined assemblies (exposed damaged tissue,often characterized as surface fibrillation due to its collagen content,exhibits deteriorating surface-layered shear properties of collagenfibril disruption and orientation changes, weak collagen-to-proteoglycanbonds, proteoglycan and lipid depletion, aberrant water content, anddecreased fixed charge density that is a suitable biopolymerdisaggregation target for protic solvents not strong enough to overcomethe normal subadjacent tissue makeup at the wound bed periphery. In thismanner, the physiochemical scalpel can produce a healthy wound bedwithout altering cell viability or residual differentiated function). Byadapting alternating current redox magnetohydrodynamics, the advantagesof protic solvents can be delivered as engineered irrigants without thedisadvantages of full enzyme system deployment typically associated withazurophilic degranulation such as myeloperoxidase and nicotinamindeadenine dinucleotide phosphate oxidase systems.

By using various saline media replacement formulations during endoscopicprocedures to express boundary conditions at normal sites,surface-confined assemblies display tribological and mechanical workingproperties governed by interfacial chemistry and a kinetic frictioncoefficient invariant to perturbations effecting fluid film formation,respectively. Capacitance balanced engineered irrigants controllablydeliver protonation potentials appropriate for boundary conditioninterfacial chemistry in order to precondition damaged tissue forremoval. The energy transduction processes of protonation coupledconformational dynamics has been shown to achieve nanometer resectionprecision through a guest chemical denaturization process below theisoelectric point of exposed damaged interstitial tissue matrices. Thisenergy transduction process utilizes low stability protonating agentsinvolved in exothermic tissue homeostasis and repair mechanisms throughdisproportionation redox reactions like those produced by therespiratory burst myeloperoxidase system activated by azurophilicdegranulation of polymorphonuclear neutrophil granulocytes during theacute phases of wound healing. Rather than relying upon localphagocytic-like processes as in acute wound healing behaviors, oncepreconditioned, damaged tissue is removed by physical implements of thedevice system appropriate for treatment interfacial mechanicalconditions through shear débridement and flushed away by the salinemedia solution. Preconditioning and removal of damaged tissue in thismanner has been a successful acute wound healing biomimic to produce ahealthy wound bed and assist differentiated biosynthetic tissue assemblyactivities in subadjacent tissue.

Although the deterioration of hydrophobicity associated with surfaceroughness can be responsible for the absence of surface-confinedassemblies at damaged sites, changes in interfacial energy andcomposition of synovial fluid likely play important complementary roles.As a manifestation of interfacial dysfunction, the inability ofsurface-confined assemblies to build on damaged tissue surfaces mayrelate to pressure-to-surface area dependent gas-gap alterations,exposed interstitial matrix negative charge density effecting hydrogenbond alterations in interfacial water, or cavitation erosion associatedwith wear particles not captured by innate removal mechanisms. Asdiscussed herein, and as in other tissue types for which irrigantseffect surface roughness, the protonation potentials generated by salinemedia replacement that self-target exposed interstitial matrices byadjacent interfacial energy discharge have been observed clinicallyduring endoscopy at articular cartilage surfaces for many decades. Thesimple observation that surface fibrillation characteristics change withdifferent replacement media provides an important clue to the clearancepotential that can be augmented by engineered irrigants through targetedbiopolymer disaggregation. This disaggregation of exposed fibrillatedtissue bathed in saline solutions accentuates the distinction betweennormal and abnormal surfaces and the resultant preconditioning remains avery plausible mechanism explaining the clinical improvements observedwith arthroscopic lavage. Increased protonation potentials likewise havebeen demonstrable within synovial fluid alterations that occurcommensurate with disease; altered synovial fluid composition in theseinstances manifests as a large endogenous wound exudate deliveringincreased protonation potentials when damaged tissue removal isrequired. By preconditioning damaged surface tissue to facilitateremoval, disaggregated debris by increased synovial fluid protonationpotentials can be delivered to the long-known mechanisms of synoviocytephagocytosis.

For articular cartilage, older technologies enabling palliative tissueresection have been deemed inappropriate for wound healing because ofunavoidable volumetric and functional over-resection that simplyexpanded lesion size, eliminated structurally stratified healingphenotypes, and left a residual damaged tissue surface in no waysuitable for the nucleation, reformation, growth, or maintenance ofsurface-confined assemblies. Concerns that such palliative approachesprovoke disease progression have understandably led to reconsiderationas to whether these treatments provide any benefit toward wound sitebioburden control even when used only to achieve short-term symptomaticrelief. While articular cartilage has shown many of the wound healingbehaviors associated with homeostatic and repair activity at itssurfaces, it is unable to remove macroscopic damaged tissue from itssurface in any meaningful way. This clearance deficiency is largely dueto the unique avascular structural transport properties and synovialenvironment of articular cartilage, both of which alter typicalinflammatory processes and the ability to localize effective woundhealing exudates aside from altered synovial fluid composition whenviewed as a form of wound exudate. Because an effective clearanceprocess is important during the acute phases of wound healing, thisdeficiency has frustrated the efforts to create a healthy lesion sitewidely considered important for both primary and secondary intentionarticular cartilage wound healing.

Similar to the fundamental cancer observation that abnormal cell growthkinetics could serve as a therapeutic trait-targeting substrate topreserve healthy tissue and enable substantial disease burdenmitigation, surface-confined nanoscale assemblies are likewise providingthis opportunity for conditions like osteoarthritis. Althoughhomeostatic and repair capacities may be decreased in areas surroundingdiseased articular cartilage as in other tissue types, partial thicknesslesions by definition contain viable cells and residual tissue functionso that creating conditions favorable to the responsive capacity ofsubadjacent tissue allows that tissue the opportunity to mountunencumbered differentiated homeostatic and repair responses. Forjuxtaposed tissue surfaces requiring relative motion such as articularcartilage, a therapeutic focus upon partial-thickness lesion woundhealing by secondary intention will likely augment recent approachesstudying primary intention wound healing as applicable to full thicknesslesions; understanding interfacial behavior can better enable tissuesurface host-to-implant integration and reconstruction of suitablesurface wear properties. Secondary intention wound healing approaches,while typically dependent upon exudative processes, seek preservedsubadjacent tissue because of tissue loss that occurs with damage. Whileassisting the limited or acquired clearance deficiency, alternatingcurrent redox magnetohydrodynamics has been shown to achieve otherimportant secondary intention wound healing effects, including wound bedcontraction that increases cell/matrix enrichment ratios and inductionof tissue assembly responses accessing genomic control mechanisms,useful to provocate post-treatment wounding healing as interfacialproperties are re-established toward a better bearing surface.

Further scope of applicability of the present invention will be setforth in part in the detailed description to follow, taken inconjunction with the accompanying drawings, and in part will becomeapparent to those skilled in the art upon examination of the following,or may be learned by practice of the invention. The objects andadvantages of the invention may be realized and attained by means of theinstrumentalities and combinations particularly pointed out in theappended claims.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the Office upon request and paymentof the necessary fee.

The accompanying drawings, which are incorporated into and form a partof the specification, illustrate one or more embodiments of the presentinvention and, together with the description, serve to explain theprinciples of the invention. The drawings are only for the purpose ofillustrating one or more preferred embodiments of the invention and arenot to be construed as limiting the invention. In the drawings:

FIG. 1 illustrates a representative post-treatment integrated Live/Deadcell viability stain section image demonstrating viable chondrocytes.

FIG. 2 illustrates a representative two photon confocal composite imageof Hoechst stained chondrocytes with the tomographic z-axis imagescompressed into a single image.

FIG. 3A-C illustrates a representative BioView images used to assessthree dimensional chondrocyte distribution patterns.

FIG. 4 illustrates R_(260/280) values versus time.

FIG. 5 illustrates RT-PCR results depicting mean fold changes intranscriptional expression of versican, COL2A1, and HSPA1A mRNA insubadjacent surface chondrocyte after non-ablation radiofrequency lesionstabilization.

FIG. 6 illustrates curve fit regression depicting transcriptionalup-regulation in subadjacent surface chondrocyte after non-ablationradiofrequency lesion stabilization.

FIG. 7A-F illustrates a medical device according to one embodiment ofthe present invention with an alternating current redoxmagnetohydrodynamic proton pump producing an irrigant within waterengineered for treating targeted tissue.

FIG. 8 illustrates a poynting vector demonstrating field-forcesummations.

FIG. 9 illustrates an electrochemical potential versus power delivery.

FIG. 10 illustrates an artistic illustration of biologic trait-targetingfor a geographically contained tissue surface based lesion.

FIG. 11A-B illustrates Depiction of charged specie movement in a directversus alternating current electric field.

FIG. 12: Tissue rescue algorithm according to one embodiment isillustrated.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The following definitions are used herein unless a symbol is defineddifferently in the context of a specific use, paragraph or equation.

As used herein “a” means one or more.

As used herein “Δp” is chemiosmotic potential.

As used herein “F” means Newtonian Force, measured in Newtons (N) forthis exercise. Recall that

${1\; N} = {1{\frac{{kg}*m}{s^{2}}.}}$

As used herein “Q” means electrical charge of a particle, direction andmagnitude depending on valence. Measured in Coulombs (C).

As used herein “E” means electrical potential, measured in Volts/meter

$\left( {{1\; V} = {1\frac{N*m}{C}}} \right).$

As used herein “υ” means measured in meters/second

$\frac{m}{(s)}.$

As used in an equation “a” means measured in meters/second²

$\frac{m}{\left( s^{2} \right)}.$

As used herein “F=Q*(E+υ×B)” means the force of a particle is equal tothe product of the charge of that particle (Q) and the sum of theelectrical field (E) and the cross product of the velocity of theparticle (υ) and the magnetic field (B).

As used herein “F=m*a” means the force on an object is equal to theproduct of the mass and the object's acceleration.

As used herein “V=I*R; P=VI” means Ohm's law and the power law.

As used herein “m_(e)” means 9.109×10⁻³¹ kg. Periodic Atomic weight(g/mol) divided by Avagodro's Number (6.022×10²³).

As used herein “m_(H)” means 1.67×10⁻²⁷ kg. Periodic Atomic weight(g/mol) divided by Avagodro's Number (6.022×10²³).

As used herein “m_(O)” means 2.66×10⁻²⁶ kg. Periodic Atomic weight(g/mol) divided by Avagodro's Number (6.022×10²³).

As used herein “m_(OH)” means 2.83×10⁻²⁶ kg. Sum of mass of O+Hydrogen.

As used herein “m_(Na)” means 3.82×10⁻²⁶ kg. Mass of a sodium ion insaline solution.

As used herein “m_(Cl)” means 5.89×10⁻²⁶ kg. Mass of a chloride ion insaline solution.

As used herein “Q” means (+/−) 1.60×10⁻¹⁹ C. Single unit of charge.

An inverse mass ratio battery (IMRB) may be used to accomplish varioustissue rescue treatments which include but are not limited to precisionresection; microfluidic mixing, stirring, and pumping; facilitativecolloidal crystal, hydro- and sol-gel self-assembly; electrolyzableinterfacing agent modification; charged species injection and migration;electromagnetic induction coupling; electro-wetting, -formation, and-swelling; micelle and coascervate formation; pharmaceutical agentdelivery; electromagnetic phoresis; extracellular matrix modification;and biosynthetic transcription initiation. Tissue surface based medicalconditions using well established endoscopic access procedures thatutilize saline solutions comparable to that within which biologic tissueresides will benefit from a system and method as disclosed herein.

One embodiment of the present invention utilizes an IMRB which is anenergy source generated in situ during treatment by inducing chargedspecie separation in saline solutions through an energy conversionprocess patterned after common biologic electron transport chainmechanisms that form proton gradients. According to one method fortreating targeted tissue, localized alternating current circuits arepositioned in saline solutions containing electroactive species to moveelectrons between device electrodes utilizing electron donor andacceptor carriers within the host fluid. This electron transportproduces fuel cell like reversible redox reaction pairs associated withcharged specie intermediaries formed above baseline solutiondissociation rates. The reaction dynamics are influenced by theattendant alternating current non-ionizing electromagnetic field quanta.

These influences include charged fluid acceleration that createmagnetohydrodynamic propulsive thrust currents. Although traditionallyused to propel the originating source, by changing the observationalreference frame, the thrust currents are adapted for medicaltherapeutics as irrigants. These “irrigants within water” are comprisedof regional structure altered molecular water exhibiting differentialcharged specie separation that results in a sequestered energy sourcecontained within the irrigant that is useful for surgical work. Becausebiologic tissue resides in a saline solution milieu redoxmagnetohydrodynamic phenomena have been deployed to alter thesesolutions to create motive delivery gradient originating from a medicaldevice.

It is thought that the energy conversion process from electron transportto charged specie separation within the attendant non-ionizingelectromagnetic environment is governed by the charge-to-mass ratio(Q/m) profile of saline solution constituents whereby those species withthe highest Q/m generally travel furthest in host media. In one example,the IMRB is generated from NuOrtho Inc.'s Engineered Irrigants™solutions. IMRB may be generated by a proton gradient formed in salinesolutions which predominantly contain charge equivalent monovalentanions and cations. For instance, sodium (or potassium) chloridesolutions contain predominantly Cl⁻, OH⁻, Na⁺ (or K⁺), H⁺, and H₃O⁺ forwhich the charge magnitude of the Q/m ratio is eliminated duringdifferential charge specie separation analyses of alternating currentredox magnetohydrodynamic phenomena. This elimination enables the designformulation of irrigant differential charge specie movement to be basedupon mass only, a feature that led to these energy sources beingdesignated as IMRB.

Referring now to one embodiment of the present invention, aphysiochemical scalpel that functions as an alternating current redoxmagnetohydrodynamic proton pump form of energy sequestration is utilizedwhich maintains regional proton gradients within the saline solutionsambient to biologic tissues. Referring now to FIG. 7A-F, the creation ofan irrigant engineered in saline solutions useful in the IMRB isillustrated according to one embodiment of the present invention. Staticimages obtained from digitized videography are depicted from left toright at 0 Watts; 25 Watts; 50 Watts; 75 Watts; 100 Watts; 120 Watts.Note that early non-soluble gas (bubble) production does not begin until35 W after which the non-soluble gas production level remainedconsistent without overwhelming the dynamics of the primary reactionzone until 75 W when the turbulence and mass effect of the increased gasproduction facilitated the removal of the reactants products from theprimary reaction zone more dramatically. Because the intermolecularhydrogen bond stretching frequencies of water demonstrate a proton basedfemto- to pico-second oscillation period, electron movements associatedwith alternating current polarity changes are less rapid so that waterprotons in the irrigant experience direct current forces (10¹²⁻¹⁵ Hzoscillation rate versus 10⁵⁻⁶ Hz circuit frequencies) during deviceactivation. Accordingly, irrigant batteries generated through motiveproton delivery gradients can be reduced to a direct current energystorage model capable of direct current discharge during contact with aspecific therapeutic target.

Alternating current (AC) electron movement produces a repetitivemolecular energy conversion loop fuel cell in saline solutions involvingsalt bridge catalyzed splitting and reconstitution of the watermolecule. The thermochemical redox reaction pair can be represented as

$\begin{matrix}{{{\alpha H}_{2}O_{(l)}} + {\beta\;{{XCL}\overset{energy}{\longleftrightarrow}\left( {\alpha - \beta} \right)}H_{2{(g)}}} + {\frac{\;\left( {\alpha - \beta} \right)}{2}O_{2{(g)}}} + {\beta HCl}_{({aq})} + {\beta\;{X{OH}}_{({aq})}}} & (1) \\{{\left( {\gamma - \delta} \right)H_{2{(g)}}} + {\frac{\left( {\gamma - \delta} \right)}{2}O_{2{(g)}}} + {\delta HCl}_{({aq})} + {\delta\;{{X{OH}}_{({aq})}\overset{energy}{\longleftrightarrow}{\gamma H}_{2}}O_{(l)}} + {\delta\;{X{Cl}}_{(s)}} + \Delta} & (2)\end{matrix}$with the variables α, β, γ, and δ as the molar quantities that satisfythe oxidation reduction requirements for the overall reaction set and Δas the available heat and/or electrical energy. Attendant non-ionizingelectromagnetic field quanta influence this redox reaction pair to movereactant and product charged species formed above baseline solutiondissociation rates away from the device electrodes and directionalizedby a plenum. Without reconciling reference frame transformations, whencharged species move in electric and magnetic fields, the following twolaws apply, the Lorentz force and Newton's second law of motion, whichcan be equated as follows

$\begin{matrix}{F = {Q\left( {E + {v \times B}} \right)}} & (3) \\{F = {{ma} = {m\frac{dv}{dt}}}} & (4) \\{{\left( \frac{m}{Q} \right)a} = {E + {v \times B}}} & (5)\end{matrix}$

Where, for equation lines (3), (4) and (5), F is the force applied, E isthe electric field, B is the magnetic field, t is time, and v, m, a, Qare the velocity, mass, acceleration, and charge of the species,respectively.

In examining the molecular dynamics of an irrigant proton transportgradient that results in energy sequestration, the intermolecularhydrogen bond stretching frequencies of water allow system treatment asa direct current model. As such, the low magnetic field curl component(v×B) in this system (alternating current redox magnetohydrodynamicsystems deploy electromagnetism rather than permanent magnetism asutilized in other magnetohydrodynamic system configurations; therefore,the magnetic component can be varied based upon the amount of electriccurrent or duty cycle utilized. Depending upon the generator energyconfiguration required for particular device system goals, the magneticcurl component can be inconsequential to treatment venue, or in otherinstances, can induce therapeutic eddy currents requiring mixed modelingtechniques), which is principally orthogonal to the electromotive force,can be condensed so that charged specie movement is reduced to a singledimension model see for example FIG. 8.

Referring now to FIG. 8, representative Poynting vector illustrationdemonstrating field-force summations. Magnetohydrodynamic propagationforces {right arrow over (N)} are applied to working fluids that entersa device plenum according to one embodiment of the present invention atpoint E so that charged specie and host fluid carrier momentum thrustsin the exit direction of the plenum opening face. The vector field linesN′ depict overall trajectories due to charge density variances betweenthe electrode edge versus its face. Note that the angular momenta andassociated torque force densities about the propagation axis are notshown. The plenum opening egress/ingress dimension area ratio asdepicted is 2.16.

By equating charged species acceleration and distance traveled

$\begin{matrix}{a = \frac{QE}{m}} & (6) \\{d = {at}^{2}} & (7) \\{d = {\frac{QE}{m}t^{2}}} & (8)\end{matrix}$

the relative scale travel distance between two different chargedspecies, x and y, can be depicted as

$\begin{matrix}{\frac{d_{x}}{d_{y}} = \frac{\frac{Q_{x}{Et}^{2}}{m_{x}}}{\frac{Q_{y}{Et}^{2}}{m_{y}}}} & (9)\end{matrix}$

Since Q, E, and t are the same for x and y as charge equivalentmonovalent species, during reactions (1) and (2), relative scale traveldistances for can be represented as the inverse mass ratio defined as

$\begin{matrix}{\frac{d_{x}}{d_{y}} = \frac{m_{y}}{m_{x}}} & (10)\end{matrix}$

Table 1 presents inverse mass ratios of predominant charged species in asodium chloride solution reflecting the formation of a proton gradientbased upon differential charged species movement.

As regional proton concentration differentials increase above normalsolution dissociation rates due to the magnetohydrodynamic pumpingmechanism, an electrochemical gradient develops from the resultantcharge separation. In settings like this wherein protons are availablefor movement, pH is a useful in situ measure of electrochemicalpotential as it can be monitored by practitioners in order to titrateeffect during treatment.

Referring now to FIG. 9, experimental data of irrigant electrochemicalpotential versus power delivery as a function of pH is illustrated.R²=0.311; p<0.02. The goodness-of-fit linear regression is better forthe segment during which low level non-soluble gas formation occurs(35-75 W) with increasing scatter as primary reaction zone turbulenceincreases within the device plenum and that R² values can be variedbased upon plenum architectural design. Data from sodium chloridesolutions (300 mOsm/L) at 20° C. with alternating current from 5 to 120W with an 8500 V peak-to-peak setting (4250 peak voltage) and 390 kHzdamped sinusoid bursts with a repetition frequency of 30 kHz into 500ohms. Because the electrochemical potential is representative ofdifferential charged specie separation and directly correlates withpower delivery, in situ measures of pH are associated with irrigantenergy.

Referring now to Table 1, an inverse mass ratio and relative scaletravel distances between predominant charge equivalent monovalentspecies predominantly present in sodium chloride solutions isillustrated. N_(A) is Avogadro's number. Comparison between predominantcharged species present in the reaction venue during creation of anEngineered Irrigant relative to the H⁺. Note that the charge valencemagnitude of each species is equal so that the inverse mass ratiorepresents

$\left( \frac{d_{x}}{d_{y}} \right);$evaluation of an x²⁺ species would require reintroduction of Q.

The proton motive force or chemiosmotic potential that is generated bythe proton gradient system is represented as the sum of the pH gradientand resultant voltage potential

$\begin{matrix}{{\Delta\; p} = {\frac{\left( {{- 2.303}\mspace{14mu}{RT}\mspace{11mu}\Delta\;{pH}} \right)\;}{nF} + {\Delta\psi}}} & (11)\end{matrix}$and the total Gibbs free energy available from a proton gradientirrigant in an open system isΔ_(i) G=−2.303RTΔpH+nFΔψ  (12)where R is the universal gas constant (8.315×10⁻³ kJ/mol-K), T is theabsolute temperature (° K), n is the number of electrons transferred; Fis the Faraday constant (96.48 kJ/V-mol), and ψ is the voltage gradientor voltage potential. Like biologic energy management systems, therelative contributions between the pH gradient (ΔpH) and the voltagepotential (Δψ) for overall Δ_(i)G is specific for particular EngineeredIrrigants. For example, in an illustrative treatment setting thatgenerates an irrigant pH gradient of 0.10 and voltage potential of0.010V at a room temperature of 25° C., the inverse mass ratio batterywould yield a free energy change of 0.57 kJ/mol for the maintained pHgradient and 0.97 kJ/mol for the created voltage gradient. Combined, thetotal 1.54 kJ/mol reflects the Δ of equation (2) for a particular redoxreaction pair conversion loop that generates a proton gradient. For apractitioner who changes the pH gradient from a to b during treatment,ΔpH is directly proportional to the irrigant Δ_(i)G being deployed

$\begin{matrix}{\frac{\Delta\;{pH}_{a}}{\Delta\;{pH}_{b}} = \frac{{{{\Delta\;}_{i}G_{a}} - {{nF}\;{\Delta\psi}_{a}}}\;}{{{\Delta\;}_{i}G_{b}} - {{nF}\;{\Delta\psi}_{b}}}} & (13)\end{matrix}$

A system and method of an embodiment of the present invention employsalternating current redox magnetohydrodynamics thereby eliminating largegenerator current impulses and minimizing electric current depositioninto tissue. These features aid to eliminate the two most common causesof iatrogenic collateral tissue damage. This embodiment is able tocapture, direct, position, and move a fluid constituent to tissuesurfaces as a therapeutic agent without extended cumbersome channelstructures for guidance. The transport is controlled with redoxchemistry and which can be turned on and off strategically. The productsgenerated can be flushed away rapidly by the host bulk endoscopic salinesolution at the practitioner's convenience. The system for use intherapeutic treatment of targeted tissue and its method of use may beapplied to such conditions as osteoarthritis so as to reduce diseaseburden.

Attendant non-ionizing electromagnetic field quanta superimposed uponalternating current formed charged species is an energy transfer processanalogous to common biologic energy management methods wherebyoxidation-reduction electron transport chain reactions enable certaincharge carriers to pump protons. In most biologic systems, themechanisms for maintaining proton charge separation are physicalmembranes or boundary coascervates at which ΔpH and Δψ may actindependently or jointly depending upon the specific transportmechanisms in operation. For example; characteristics perhaps not moreclearly demonstrated by the differences between mitochondria andchloroplast membranes. While irrigants engineered viamagnetohydrodynamics to maintain charge separation, differences inrelative contribution from ΔpH and Δψ to overall Δ_(i)G can be likewisedesign formulated for specific indications. A significant advantage ofthe IMRB resides in the simplified design formulation for proton pumpingstoichiometry. Charge equivalent monovalent species uniquely relate tothe Nernst n in equations (11) and (12) so that the number of protonscompared to the number of positive charges moved per electrontransported (i.e. monovalent Goldman-Hodgkin-Katz treatment) during thealternating current half cycle more directly correlates with the in situpH changes that are useful to monitor during treatment. Multivalentspecies can have a profound effect on the ability to form and dischargea proton gradient. Further, these species also affect tissue surfaces,much like their behavior at the electrical double layer that forms onmicro and nanofluidic device surfaces, by altering charge interactionsand interfacial energy.

Normal tissue surfaces demonstrate phase-state transition properties.This is akin to this electric double layer, being comprised of abiologic exclusion zone proton gradient formed adjacent to hydrophilicbiohydrogel phospholipid oligolamellar layers which manage interstitialmatrix wettability and surface charge barriers. Although generated by adifferent mechanism, the IMRB exhibits similar energy storage featuresto that of the biologic exclusion zone proton gradient. Irrigantsengineered with proton gradient energy is designed to be of similarmagnitude to normal tissue surface interfacial proton gradient energy sothat varied capacitance between the two energy sources does not lead tosignificant discharge of either during treatment. These damaged surfacesare devoid of hydrophilic biohydrogel layers because of increasedroughness and decreased wettability. Consequently, the biologicexclusion zone proton gradient cannot form appropriately upon theexposed hydrophobic interstitial matrices. In these locations, the IMRBenergy is consumed through the fixed negative charge density of theexposed interstitial matrix as a protonating force. Since both theirrigant and interfacial batteries are based upon proton gradients inwater which demonstrates fast intermolecular bond oscillation rates,trait-targeting energy can be modeled as a direct current supercircuitrepresented by instantaneous voltage energy transfers.

As designed for use with a physiochemical scalpel, the IMRB energycapacity is customized to achieve nanometer resection precision througha chemical denaturization process below the isoelectric point of exposeddamaged interstitial tissue matrices. This therapeutic process wasadapted from a biologic treatment hint offered by polymorphonuclearneutrophil granulocytes; wherein, their respiratory burstmyeloperoxidase system produces low stability protonating agentsinvolved in exothermic tissue homeostasis and repair mechanisms throughdisproportionation redox reactions. Because of high proton motilities inwater, stoichiometric protonation β↓(H↓n); β_(H) _(n) is the cumulativeprotonation constant for the addition of the n^(th) proton for theformation of H_(n)P from nH⁺ and P, where P is an interstitial matrixprotein or polymer complex. The energy transduction processes ofprotonation (coupled conformational dynamics) is a very rapid chargeredistribution process that leads to biopolymer disaggregation throughmolecular cleavage planes accessible due to normal tissue surfacebarrier losses and degenerate matrix properties. Irrigant protonrecruitment and pressure force modeling for a commonly deployed 25 Walternating current input of one embodiment of the present inventiondemonstrated the movement of 5.3×10¹¹ protons per 1.3 μs half periodyielding 2.8 mmHg. This protic solvent pressure force is similar inmagnitude to the transcapillary net filtration gradient required togenerate normal net capillary filtration and facilitates irrigant accessinto damaged interstitial matrices at an energy level sufficient tochemically denature diseased collagen-proteoglycan matrices and bringabout nanometer level resection precision.

One aspect of one embodiment of the present invention provides forresection precision which guards against volumetric and functionalover-resection. Over-resection can contribute to disease burden.

Redox magnetohydrodynamic engineered irrigants (transportable regionallystructure-altered fluids or water) are based upon constituentcharge-to-mass ratio profiles: radiofrequency electromagnetic energyproduces a Lorentz force generated proton delivery gradient in salineassociated with biologic-appropriate motive forces.

These gradients impact a specific tissue target by locally altering thesaline solutions. Engineered Irrigants are created by positioninglocalized alternating current circuits in saline solutions to produceredox reaction pairs upon which attendant non-ionizing electromagneticfield quanta influence reaction dynamics (see for example FIG. 7).Although charged species, like material particles and ions, generatetheir own electric and magnetic fields, disclosed herein are systems,methods and examples of irrigants engineered therewith throughLorentzian relative scale modeling of venue-specific charged speciesbased upon useful in situ biologic measures of electrochemicalpotential.

For example, sodium chloride solutions (300 mOsm/L) at 25° C. weretreated with alternating current from 10 to 120 W with an 8500 Vpeak-to-peak setting (4250 peak voltage) and 390 kHz damped sinusoidbursts with a repetition frequency of 30 kHz into 500 ohms. This deviceconfiguration produces the redox reaction pair

$\begin{matrix}{{{\alpha H}_{2}O_{(l)}} + {\beta\;{{XCL}\overset{energy}{\longleftrightarrow}\left( {\alpha - \beta} \right)}H_{2{(g)}}} + {\frac{\;\left( {\alpha - \beta} \right)}{2}O_{2{(g)}}} + {\beta HCl}_{({aq})} + {\beta\;{X{OH}}_{({aq})}}} & (14) \\{{\left( {\gamma - \delta} \right)H_{2{(g)}}} + {\frac{\left( {\gamma - \delta} \right)}{2}O_{2{(g)}}} + {\delta HCl}_{({aq})} + {\delta\;{{X{OH}}_{({aq})}\overset{energy}{\longleftrightarrow}{\gamma H}_{2}}O_{(l)}} + {\delta\;{X{Cl}}_{(s)}} + \Delta} & (15)\end{matrix}$with the variables α, β, γ, and δ as the molar quantities that satisfythe oxidation reduction valence requirements for the overall reactionset. Without reconciling reference frame transformations, when chargedspecies move in electric and magnetic fields, the following two lawsapply, the Lorentz force and Newton's second law of motion, which can beequated as follows:

$\begin{matrix}{F = {Q\left( {E + {v \times B}} \right)}} & (16) \\{F = {{ma} = {m\frac{\mathbb{d}v}{\mathbb{d}t}}}} & (17) \\{{\left( \frac{m}{Q} \right)a} = {E + {v \times B}}} & (18)\end{matrix}$where F is the force applied, E is the electric field, B is the magneticfield, and v, m, a, Q are the velocity, mass, acceleration, and chargeof the species, respectively. Referring now to FIG. 11A, depiction ofcharged specie movement in a direct versus alternating current electricfield is illustrated. Alternating current magnetic fields cause curlforces in an orthogonal direction to the electric field similar to theright hand rule for circuits. Due to intermolecular bond dynamics ofwater, combined with device configuration, the magnetic component forthe purposes of this engineering level relative scale analysis isreduced to condense the analysis to electric field influences. FIG. 11B,illustrates line art depicting proton build-up due to differentialcharged species movement depicting the positive half of the wavelengthand free H⁺ moving a much longer travel distance than OH⁻ “anchored” bythe heavier oxygen. At various travel distances, the H⁺ form heavierspecies like H₃O⁺, which are then anchored in place and won't return asfar as the H⁺ traveled outward as current polarity changes, resulting ina proton-based charge separation gradient.

Because the magnetic curl component is principally orthogonal to theelectromotive force, it adds only a very small relative distance to thefinal travel from origin due to device configuration. By reducing thiscomponent through an engineering-level analysis, charged specie movementcan be examined in a single dimension model by calculating chargedspecies acceleration and distance traveled by equating as follows:

$\begin{matrix}{a = \frac{QE}{m}} & (19) \\{d = {at}^{2}} & (20) \\{d = {\frac{QE}{m}t^{2}}} & (21)\end{matrix}$

Accordingly, the relative travel distance between two different chargedspecies, x and y, can be depicted as

$\begin{matrix}{\frac{d_{x}}{d_{y}} = \frac{\frac{Q_{x}{Et}^{2}}{m_{x}}}{\frac{Q_{y}{Et}^{2}}{m_{y}}}} & (22)\end{matrix}$

During reactions (14) and (15) in sodium chloride solutions, thepredominant reactant/product charged species present include H⁺, OH⁻,Na⁺, Cl⁻, and H₃O⁺ for which relative scale travel distances aredetermined and correlated with electrochemical potential measures duringirrigant formation. Because of widely fluctuating treatment venueconditions including numerous charge movement influences, thedifferential charged species separation resulting in electrochemicalpotential formation is modeled as proton travel distance, recruitment,and resultant pressure force as generated by a typical device systemelectric field of 3.1×10⁴ V/m in order to provide benchmark solutionparameters. [electric field model based upon average electrodeseparation of

${6.1 \times 10^{- 3}\mspace{14mu}{{m\left\lbrack \frac{{1.74\mspace{14mu}{mm}} + {10.41\mspace{14mu}{mm}}}{2} \right\rbrack}.\mspace{31mu}\begin{matrix}\; \\E\end{matrix}}\frac{V}{(m)}} = \frac{\left( {2000\mspace{14mu} V} \right)\sin\frac{t}{2.6\mspace{14mu} µ\; s}}{6.1 \times 10^{- 3}\mspace{14mu} m}$with average electric field of ½ alternating current period (1.3 μs atf=390 kHz and λ=2.6 μs) represented as

${E_{ave} = {\frac{1}{1.3\mspace{14mu} µ\; s}{\int_{0}^{1.3\mspace{14mu} µ\; s}{\frac{2000\mspace{14mu} V}{6.1 \times 10^{- 3}\mspace{14mu} m}\sin\frac{t}{2.6\mspace{14mu}{µs}}\ {\mathbb{d}t}}}}},{E_{ave} = {\frac{2000\mspace{14mu} V}{\left( {1.3\mspace{14mu} µ\; s} \right)6.1 \times 10^{- 3}\mspace{14mu} m}\left( {{- \cos}{\frac{1.3\mspace{14mu} µ\; s}{2.6\mspace{14mu} µ\; s}--}\cos\frac{0}{2.6\mspace{14mu} µ\; s}} \right)µ\; s}},\mspace{14mu}{and}$$E_{ave} = {{\frac{2000\mspace{14mu} V}{7.93 \times 10^{- 3}\mspace{11mu} µ\; s*\; m}\left( {{- {.0878}} + 1} \right)µ\; s} = {3.07 \times 10^{4}\mspace{11mu} V\text{/}{m.}}}$[Note that this estimation accepts a tenfold difference in the near andfar distances between potential field lines]. (See FIGS. 6-8).

Irrigant electrochemical potential versus power delivery is illustratedin FIG. 9 and relative travel distances between irrigant charged speciesare presented in Table 1. During energy delivery, an H⁺ (proton)electrochemical potential gradient is created representative of chargedspecie separation and is directly correlated with power delivery. Thecharged specie relative travel distances indicate that differentialproton movement is highest based upon charge/mass ratios. The resultantcharge separation functions as a redox magnetohydrodynamic proton pumpthat can be delivered to tissue surfaces through charge carriers.

From equation (8), proton travel distance in a vacuum under irrigantcreating forces is

$\begin{matrix}{{d_{H} + (m)} = {\frac{\left( {1.6 \times 10^{19}\mspace{11mu} C} \right)\left( {3.1 \times 10^{4}\frac{V}{m}} \right)}{1.67 \times 10^{- 27}\mspace{11mu}{kg}}\left( {1.3 \times 10^{- 6}\mspace{14mu} S} \right)^{2}}} & (23)\end{matrix}$which yields the result of d_(H) ₊ =5.02 m. Result obtained bysubstituting

$\left\lbrack {{1\mspace{14mu} V} = {1\frac{(N)(m)}{c}}} \right\rbrack$with

$\left\lbrack {{1\mspace{14mu} N} = {1\frac{({kg})(m)}{s^{2}}}} \right\rbrack$to yield

$\left\lbrack {{1\mspace{14mu} V} = {1\frac{({kg})\left( m^{2} \right)}{(C)\left( s^{2} \right)}}} \right\rbrack.$

By multiplying the average electric field 3.1×10⁴ V/m by the averageelectrode separation 6.1×10⁻³ m, the average voltage 189.1 V isdetermined and can be used to obtain current at a specified powersetting. For 25 W,

$\begin{matrix}{P = {VI}} & (24) \\{I = {\frac{2\; 5\mspace{14mu} W}{{189.1\mspace{14mu} V}\mspace{11mu}} = {{0.132a} = {0.132\frac{C}{s}}}}} & (25)\end{matrix}$Within the 1.3 μs alternating current half period, the irrigant creatingcurrent generates charged species as depicted by

$\begin{matrix}{\mspace{79mu}{{0.132\frac{C}{s}\left( {1.3 \times 10^{- 6}s} \right)} = {1.7 \times 10^{- 7}C}}} & (26) \\{{\#\mspace{14mu}{of}\mspace{14mu}{Carriers}} = {{1.7 \times 10^{- 7}{C \div \frac{1.6 \times 10^{- 19}C}{\#{ofChargeCarriers}}}} = {1.1 \times 10^{12}}}} & (27)\end{matrix}$Assuming the carriers will be represented evenly between positivecharges (such as H⁺) and negative charges (such as OH⁻) and that 99.1%of charge is split water, 5.4×10¹¹ charge carriers in solution produceapproximately 5.3×10¹¹ protons that move during the positive portion ofthe alternating current signal.

Because of the intermolecular hydrogen bond flicker rate of water, theforce of each proton can be modeled from equation (3) whereby

$\begin{matrix}{F = {QE}} & (28) \\{F_{H^{+}} = {{\left( {1.6 \times 10^{- 19}C} \right)\left( {3.1 \times 10^{4}\frac{{kgm}^{2}}{{mCs}^{2}}} \right)} = {5.0 \times 10^{- 15}\mspace{11mu} N}}} & (29) \\{{\sum F_{H^{+}}} = {{\left( {5.3 \times 10^{11}H^{+}\mspace{11mu}{ions}} \right)\left( {5.0 \times 10^{- 15}\mspace{11mu} N} \right)} = {2.7 \times 10^{- 3}\mspace{14mu} N}}} & (30)\end{matrix}$

In creating a designed irrigant for therapeutic application, a deviceplenum area opening of 7.2 mm² (7.2×10⁻⁶ m²) generates a proton pressurewhich can be represented as

$\begin{matrix}{P_{H^{+}} = {{2.7 \times 10^{- 3}\mspace{11mu}{N/\left( {7.2 \times 10^{- 6}\mspace{11mu} m^{2}} \right)}} \approx {370\frac{N}{m^{2}}} \approx {0.05\mspace{14mu}{psi}\mspace{11mu}\left( \frac{{lb}_{f}}{{in}^{2}} \right)} \approx {2.8\mspace{14mu}{mmHg}}}} & (31)\end{matrix}$

Electromagnetism influences the interactions between electricallycharged species thereby governing chemical processes. Although the timeand spatial responses of charges are complex, understanding theconstituents of a particular venue can allow charge separation modeling(FIG. 6). In creating irrigants designed for the targeted tissue,attendant non-ionizing electromagnetic field quanta cause a distortionof alternating current circuit reaction dynamics in saline solutionsconsistent with water's cooperative hydrogen bonding. Becauseintermolecular hydrogen bond stretching frequencies of water demonstratea proton based femto- to pico-second oscillation period, electronmovements associated with alternating current polarity changes are lessrapid so that water protons experience direct current forces (10¹²⁻¹⁵ Hzflicker rate versus 10⁵⁻⁶ Hz circuit frequencies). Accordingly, thishigh proton mobility and intermolecular dynamics of water allowsmodeling as a single dimensional direct current circuit to determinerelative scales that are pertinent for biologic applications.

Device constrained redox magnetohydrodynamic forces induced byalternating current circuits in saline solutions produce motive deliverygradients that transport protons in much the same manner as that ofbiologic proton pump mechanisms resulting from electron transportchains. The modeled pressure forces of the irrigant proton gradient aresimilar in magnitude to the transcapillary net filtration gradientrequired to generate normal net capillary filtration. Furtherconsideration to the many influences on specific charged species insaline solutions and other attractive-repulsive forces present duringtreatment are required to detail the therapeutic deployment of irrigantsengineered for electrochemical potentials. These processes producecharge separations based upon charge-to-mass ratio profiles withbiologically appropriate motive forces. These same mechanisms have beenapplied to the understanding of other biologic processes that occurduring therapeutic intervention. Based upon the foregoing, FIG. 12depicts a tissue rescue algorithm for the methods and devices describedherein. Referring now to FIG. 12, a tissue rescue energy-based device asdescribed herein 1200 according to one embodiment of patent invention,provides for early surgical intervention designed to mitigate thedisease burden of tissue surface-based medical conditions through safelesion stabilization. Alternating current 1201 at the treatment venue isdeployed via specialized device architecture that prohibitselectrode-to-tissue contact and creates a protected reaction zone.Electromagnetic field energy 1203 are non-ionizing forces produced byprecise use of specific alternating current configuration delivered intosaline solutions. Water splitting reconstitution reactions 1205 ofsaline solutions provide repetitive molecular energy conversion loopfuel cell activity and produces charged species designed for therapeuticuse. Motive thrust fluid currents 1207 move charged species towardtissue surfaces via redox magnetohydrodynamic propulsion. An energytransfer process 1209 creates an irrigant engineered to target damagedtissue surfaces as normal charge barriers are absent. The normal tissuesurface is protected 1213 and the exclusion zone and surface wettingproperties are enhanced. Irrigants engineered 1209 are directed totissue target surface 1211 and chemically denatures accessible damagedtissue preconditioning the targeted tissue for removal.

At the tissue matrix level, irrigant engineered as described in 1209,unburdens contiguous healthy tissue and creates healthy lesion siteallowing differentiated homeostatic and repair responses to occur 1215.An electromagnetic field energy 1203 induces an extra cellular matrixcontraction increases cell to matrix ration protecting pericellularmatrix 1217 and increases cell-to-matrix ratio while protectingpericellular matrix contents. At the genomic level, an electromagneticfield energy 1203 as described engages transcription initiationmechanisms associated with cellular biosynthesis 1221. Irrigantsengineered as described in 1209 induce tissue assembly responses 1219averting pathological phenotype alterations resultant from thephysiologic loading of an unhealthy site.

Even though the consequences of over-resection for tissue-surface basedmedical conditions include disease progression, early morphologicsurface changes remain an attractive therapeutic target as this settingretains the elements in situ for normal homeostasis and repair. Becauseof the resection precision required (μm-nm scale) and since tissuesurfaces reside within a saline milieu, maintaining cell viability and adifferentiated phenotype around a lesion site stabilized relative to itsperturbation specificity and modality requires knowledge ofsaline-to-tissue interfaces during disease-related changes in tissueboundary structure-function.

Accordingly, the mechanisms by which organisms construct and utilizesaline charge barriers provide a therapeutic substrate at the requisitescale from which interventions can be devised that do not injure thisbarrier at normal tissue surfaces yet take advantage of its disruptionat diseased tissue sites. This scale-appropriate trait-targetingchallenge has been met by IMRB generated and deployed irrigants thatphysiochemically loads tissue surfaces in an irrigant manner based upongerm layer independent but charge dependent mechanisms. Treatment with a“physiochemical scalpel” are methods according to one embodiment of thepresent invention designed to accelerate lesion recovery by inducingadvantageous cell-to-matrix modifications and stimulating differentiatedtissue assembly repair functions within the retained contiguous tissueutilizing irrigants engineered with proton availability from an IMRB.

When charges in fluid media are manipulated with energy, productsinclude useful molecules such as irrigants (referred to as irrigantsbecause of the fluid milieu as well as the manner in which the productsare delivered to tissues) that are created purposefully to bathetargeted tissue sites as a means to induce tissue changes specific forpreconditioning or manipulating tissue characteristics. The irrigantbath includes charge accelerations, for example, hydrogen ion (proton)delivery within the irrigant that treats tissues—like an acid shift inthe irrigant. When this charge is purposefully induced within tissues,the products may also include electromagnetic forces that affect tissuesat and below the surface level, unencumbered tissues (tissues subsequentto therapeutic intervention due to removed diseased tissue withoutcollateral damage to healthy tissue). These forces alter gene expressionby mechanisms such as electron acceleration within macromolecular tissueconstituents including DNA. The induced electromagnetic fields createrepulsive forces within molecular assemblies such as double strand ortriple strand polymers. The electron acceleration can cause strandseparation, which in the case of DNA initiates transcription at specificpromoter domains.

The manipulation of charges as explained more fully herein in eitherlocal, tissue surface or subsurface, is the charge/mass ratio, and forelectrons manipulated by radiofrequency energy, this process utilizes ahigh charge/mass ratio. The high charge/mass ratio is useful formanipulation of a fluid media, for example saline. The productsdelivered to the tissue include a shift towards acid production, whichis another way of describing hydrogen ion or proton delivery to tissuesurfaces dependent upon the acceleration of those electrons. Protons canbe carried in the media via various compounds like sodium hypochlorite.Further, a high charge/mass ratio is useful within tissues because itdoes not damage normal tissue but instead stimulates specific responsessuch as a charge acceleration creating an electromagnetic field having athreshold slightly above micro-environmental perturbation noise forexample molecular vibrations that occur naturally within the tissuestructures that we treat. A small field guards against iatrogenic injurywithin retained contiguous tissue. Further, ion exchanges are animportant process at tissue interfaces because of the chargeaccelerations that are occurring. These exchanges are induced in tissuesurface barriers, like boundary lubrication mechanisms, based upon theelement (i.e. H₂O, Na⁺Cl⁻) makeup of the irrigant fluid into which theenergy is deployed.

For example, manipulation of the phospholipid layer, the surfactantlayer, is an important mechanism to protect tissues during irrigantdelivery. Cation exchanges are utilized by altering the monovalent anddivalent cation concentration of the interfacing media. Cation ionexchanges change the properties of tissue surface barriers to eitherprotect them or to alter their properties to benefit treatment.

Proton delivery to tissue surfaces exposed to or within a fluid mediaenvironment may be driven by radiofrequency acceleration of electronsthat retain high charge/mass ratio. A high charge/mass ratio is neededso that the energy requirements to drive the acceleration of electronsis low to avoid or minimize iatrogenic injury from excessive energyinput to the body. These low energy requirements drive the createdprotons to tissue surfaces that interact with diseased biologic tissuebut are not disruptive to normal tissue surfaces. A device as describedin U.S. Pat. Nos. 6,902,564, 7,066,932, 7,819,864, 7,713,269, 7,445,619,7,771,422, 7,819,861 or 7,354,438 for example having an electrosurgicalplenum facilitates this low energy deployment.

Electron acceleration within tissues is needed because of this highcharge/mass ratio and low energy requirements. Initiating geneexpression with energy that is not injury inducing to the tissuepromotes healing of the treated tissue. The initial tissue assembly orrepair responses of cells are characteristically governed by lowthreshold excitation relative to ambient E-M fields and showresponsiveness just above environmental perturbation—this is because ofthe nature of tissue homeostasis, that cells need to respond quickly tochanges in their environment. Electromagnetic fields deployed hereinaccomplish this because of the high charge/mass ratio utilizingelectrons at a level that does not cause tissue damage at thesubsurface, but utilize normal homeostatic and repair mechanisms.

Systems and methods as described herein can be utilized for any tissuesurface based lesions, for example articular cartilage. The effects aredelivered in situ at the lesion site, rather than an external deliverylike other electromagnetic field producing devices. In one embodiment ofthe present invention, the intimate relationships between tissue surfacebarriers and their saline environments create a therapeutic substratefor the surgical rescue of diseased tissue.

One embodiment of the present invention provides for early interventionby enabling the therapeutic enrollment of contiguous tissue healingphenotypes that make lesion reversibility possible. For example,osteoarthritis results in whole joint-organ disease persuaded byarticular cartilage integrity failure. Because damaged cartilage servesas a biologic-mechanical irritant that causes symptoms and advancesdisease, treatment efforts designed for its removal remain an intuitiveand important focus intended to maintain articular cartilage integrityand alleviate disease burden. Yet, lesion stabilization has beenconstrained by surgical interventions resulting in volumetric orfunctional over-resection that expand lesion size and provoke or advancedisease progression. Despite past attempts to minimize over-resection,only recently has its elimination been enabled. Transformativediscoveries of this magnitude are often initially plagued by doubtsabout their practical value; for osteoarthritis, these value assessmentsare additionally confounded by articular cartilage's reputation as atissue type with a perceived poor healing capacity, even though thisreputation may be largely due to the retention of damaged tissueartifacts that act as a biophysical irritant in the context of thehistorical inability to avoid scale-appropriate over-resection.

Articular cartilage is a highly differentiated and stratified tissuethat retains a large portion of its adult healing phenotype at itssurfaces. Because cartilage lesions can progress slowly, reflectingretained contiguous differentiated homeostatic resistance capacityagainst the degree to which diseased tissue burden becomes overwhelming,eliminating over-resection is often viewed as a tissue rescue designedto unencumber contiguous tissue function and minimize downstreammorbidity. To preserve superficial healing properties heretofore fullyeliminated as collateral damage, surgical resection requires “vim level”precision; further, normal tissue surface barrier regimes are structuredat the “nm level”, presenting a challenging venue to guard againstiatrogenic injury. Consequently, surgical precision necessitates aunique “physiochemical scalpel” approach that includes replacingtraditional surgical visual-tactile cues with treatment endpointsborrowed from comparative explant microhistology. Although treatmentendpoint cue evolution can influence new technology adoption rates,cartilage management education toward a cognitive map is beingencouraged by socioeconomic pressures supportive of over-resection asunnecessary, harmful, and liability-laden. As it is difficult to imagineinformed patients forgoing the opportunity to preserve their tissuelonger, either by replacing cartilage lesions with larger ones or simplywaiting for diseased tissue to overwhelm contiguous differentiatedhomeostatic resistance capacity, the rapidly emergent obsolescence ofover-resection also reflects consumer pressures.

The benefits of tissue rescue to unencumber contiguous tissue functionare considerable. Prior to surmounting the over-resection treatmentbarrier that enabled tissue rescue, lesion reversibility was clinicallyinaccessible. Since contiguous differentiated homeostatic resistancecapacity can give way to the burden of damaged cartilage, tissue rescueseeks not only to unencumber contiguous tissue, but also topermit-enroll the tissues intrinsic homeostatic and repair capabilitiesto avoid irreversible phenotypic alteration or destruction. Uniquely,articular cartilage's superficial zone reveals molecular productionspecificity like clusterin, versican, and lubricin; chondrocytemigration in response to focal partial-thickness lesions; control ofzonal reorganization; appositional growth; chondroproliferation;chondrocyte colony formation; and a side population source ofmesenchymal progenitor cells that express stem cell markers, contractileactin isoforms, progenitor cell signaling mediators, and monolayerexpansion behavior while maintaining a chondrogenic phenotype. Becausearticular chondrocytes display significant phenotypic plasticity andhigh anabolic capacity, improving their environment by targeted diseasedtissue resection is an effective means to stabilize contiguouschondrogenic phenotype(s), even if that includes interrupting earlyphenotypic adaptations-alterations to disease.

As reversibility for some lesions may require a phenotypic shift(osteoarthritic chondrocyte redifferentiation) such as that induced byphysiologic loading a healthier site, the capability to transientlyupregulate focal chondrocyte biosynthetic activity reflective ofdifferentiated tissue assembly repair mechanisms remains an importantearly post-treatment therapeutic desire.

Inducing in situ, targeted, appropriate, and differentiated biosyntheticcellular function within contiguous tissue subadjacent to diseasedlocales and thereby recruiting local chondrocytes to aid lesionrecovery, requires the ability to access genomic control. Thesemechanisms that govern tissue assembly and display promoterdomain-segment threshold responsiveness slightly abovemicro-environmental perturbation noise. As such, in vivo transcriptioninitiation technology based upon charge/mass ratio dependentacceleration characterizes a revolution of function and enabledpossibility for cartilage. Because of the enormous health gains to berealized by reducing osteoarthritis disease burden, the goal ofunencumbered contiguous tissue and lesion reversibility becomes aneffort difficult to ignore, despite cartilage lesion heterogeneity thatmay require nuanced device design.

Another example is directed to hyaline cartilage commonly encounteredduring arthroscopy for which the system and method of embodiments of thepresent invention may be applied. Early articular cartilage damagemanifests as surface matrix changes such as that observed with theinitial stages of osteoarthritis. Despite the heterogeneity of thisdamage, safe lesion stabilization (i.e. damaged tissue removal) isrequired to permit intrinsic homeostatic and repair responses sincedamaged tissue serves as a biologic and mechanical irritant impedingsuch responses and leading to symptoms and disease progression. Lesionstabilization for early articular cartilage disease constitutes a tissuerescue, allowing biologic tissue response properties to more fullymanifest unencumbered rather than allowing the tissue to progressivelyconvert to a mechanical adaptation construct characterized by furthermatrix failure. Because early intervention presupposes that tissuesurrounding the lesion retains effective differentiated function,therefore chondrocyte viability and a healing phenotype are importantattributes to retain within subadjacent tissue.

Thermal and plasma ablation technologies which deliver electricalcurrent directly into tissue have been deemed inappropriate forarticular cartilage tissue preservation procedures as a result ofsignificant induced iatrogenic damage to subadjacent tissue associatedwith the high energy deployment necessitated by device design. Hyalinecartilage is a tissue type retaining a high water content ensuring thatablation technology will effectively pool electrothermal energies withincartilage tissue to a detrimental level. Ablation technologies cannotdistinguish between normal and abnormal tissues because device design isnot based upon tissue specific biology and consequently induce necrosis.This necrosis is caused for a variety of reasons, including theformation of subsurface tissue heat capacitance due to waterpermeability constraints at normal surfaces adjacent to lesions, theoverwhelming metabolic disturbances of internal tissue electrolysis, andthe surface entry wounds typical of electrical injury; all of whichfurther impair tissue integrity and local biologic responses byexpanding the size of the original lesion and further progressingdisease. Non-ablation technology allows for the targeted removal ofdiseased tissue without expanding lesion size or compromising subsurfacetissue with electrical current deposition.

Device architecture of one or more embodiment of the present inventionensures that the near-field reaction products are delivered only totissue surfaces, not within tissues, and can selectively target damagedtissue, preparing it for mechanical débridement through inherentcleavage planes. Diseased articular cartilage is characterized bydeteriorating surface-layered shear properties of collagen fibrildisruption and orientation changes, weak collagen-to-proteoglycan bonds,proteoglycan depletion, aberrant water content, and decreased fixedcharge density; this compromised tissue is further altered by thephysiochemical loading delivered by non-ablation technology to a stateamenable to gentle shear débridement during lesion stabilization. Shearstabilization in this instance illustrates treatment design relative toa tissue's perturbation failure specificity; understandably, safe lesionstabilization remains an advance inextricably necessary for diseaseburden mitigation.

The role of water at surgical treatment sites is an important factor toconsider because of its ubiquitous presence in biologic assemblies.Tissue preserving surgical procedures can be difficult to create sincethey require balancing macroscopic treatment events with microscopicphysiologic function. For example, many surgical treatment venues resideat tissue surfaces due to tissue integrity failures originating fromsurface forces or processes overloading tissue capacity to maintainintegrity. Intact surfaces, whether articular cartilage, tendon,ligament or even other representative tissue types like gastric mucosaor lung pleura, are structured by water, often through variations inhydrophobic adhesion, to create a protective barrier designed tomaintain tissue integrity against tissue-specific perturbations whilemaintaining lubrication zones that protect the underlying tissue matrixstructure. Surface active phospholipid organization and absorption intolamellar superficial collagen layers constraining proteoglycan moietiesis a common finding at the water-to-tissue interface that create therobust physiochemical charge barrier of tribiologic systems. Thesesurface active phospholipid layers are often amorphous (withoutcollagen), non-fibrous, or gel-like and can reconstitute viaself-assembly after removal. These can reconstitute even after removaldeep to collagen layers, through polymorphic aggregation forces like thehydrophobic effect governed by water. It is interesting to note thatmany anatomic tissue surface sites subjected to repetitive perturbationhave similar tissue homeostatic and repair mechanisms. These mechanismsallow for collagen based layered or cleavage plane failure as a back-upmechanism to topographic loss of water-structured amorphous surfacebarrier regimes that can occur during physiologic loading. Thissurface-based collagen cleavage plane failure is generally a reversiblelesion under certain circumstances, most notably with damaged tissueremoval while maintaining cell viability and differentiated phenotypearound a lesion site stabilized relative to perturbation specificity.

Non-ablation technology exploits this common tissue surfacecharacteristic for tissue preserving lesion stabilization by augmentingthose structural planes during selective preconditioning or modificationof diseased tissue that has become accessible due to the loss of thesurface regime barriers. It is further interesting to note that thesenormal tissue surface regimes are rather robust because of water'sstructural interfacial organization, such that the reaction productsoriginating from the electrosurgical plenum at tissue preservationsettings cannot disrupt this barrier. Hence, undamaged surface tissue isprotected. Indeed, disruption requires prolonged perturbations likeenzymatic incubation, strong detergents, large single or cumulativeinsults, or even ablation energies. Additionally important is that thehealthy bed of lesions being stabilized is also a barrier to suchtreatment due to the integrity of those same tissue constituents whichwhen diseased are susceptible to tissue specific non-ablationphysiochemical loading regimens.

Tissue edema, or an increase in tissue water content distinct fromtissue surface water, is often an early event associated with injury ordisease occurring prior to observable morphological changes. Theincreased water content can be due to either an alteration in tissueconstituent structure or the re-localization of additional tissuecomponents. Surgical targeting of tissue with an increased water contentbut without observable macroscopic alterations remains difficult. It isfor this reason that most surgical device development is based uponobservable criteria that the surgeon can readily identify during theprocedure. Surface-based morphologic changes are uniquely suited as atherapeutic target, particularly since early intervention in thesesettings is governed by the ability to pursue tissue rescue as a resultof creating an environment amenable at least to homeostasis and at bestto self-repair.

The use of an electrosurgical plenum serves many functions, one beingprimary reaction zone manipulation within its interior. Configurationchanges in its architecture can alter the formation and delivery ofreaction products during targeted physiochemical loading of tissuesurfaces. Two reaction products, pH and temperature, were evaluatedbecause they are especially relevant to the function of water at tissuesurfaces during physiochemical loading in a sodium chloride milieu, eventhough many other associated physiochemical phenomena are simultaneouslyoccurring and warrant description.

For instance, a purposeful change in pH can be configured toward astrict linear regression by further shielding the primary reaction zonefrom the fluid-flow and convective forces at the treatment site. Thetemperature at the tissue or the media that interfaces with the issuecan be manipulated. For example, heat can be delivered to tissuesurfaces by creating localized temperature changes in the interfacingmedia rather than within the tissue itself as occurs with ablationtechnologies. Water has a high specific heat capacity and heat ofvaporization therefore, it buffers heat delivery in a protective manner.Purposeful modulation of reaction product that escapes from the primaryreaction zone coupled with a surgical intervention that is dependentupon positioning of an electrosurgical plenum of a electrosurgicaldevice as previously described in U.S. Pat. No. 7,819,861 is a usefulprocess to control the character such as duty-cycle, pH shift,ion-specific delivery and the like of treatment-specific reactionproduct that is delivered to tissue surfaces during physiochemicalloading.

In one embodiment of the present invention, temperature change as afunction of initial interfacing media temperature has been designed toprotect tissue surfaces from inadvertent temperatures that may have anundesirable efficacy. While tissue surfaces, like phospholipid layers,can be sensitive to temperature changes, a device as employed in oneexperiment was designed to induce only a small temperature change of theinterfacing media with a protective triphasic behavior. Further tissuepreserving settings may be employed within Phase 1 (for example, lowenergy phase typically below 35 W with no significantoxidation/reduction gas generation during which no temperature change isdeployed).

In addition to the protective role that ambient water serves duringnon-ablation treatment of legions as described herein, it also serves aprotective role at tissue surfaces because the water is absorbed andheld by tissue surface constituents. These tissue surfaces are robustdue to water's influence on their constituents' polar regions withpositively charged ends anchored to the negative charge density ofproteoglycan typical in collagen constrained extracellular matrix. Forexample, hydration shells around phospholipids bind water via hydrogenand electrostatic bonds and when combined with hydrated ions becomeeffective lubricants between sliding charged surfaces. This compositioncreates a strong laterally bonded network that is protective againstshear forces by exhibiting lipid mobility and viscous resistance.

For physical load bearing tissue, the surface amorphous layer cansupport the majority of a load within its water phase thereby alteringthe liquid-solid phase load sharing of subsurface tissue by protectingthe solid phases from elevated stresses. This water-to-tissueinterfacial phenomenon is important in boundary lubrication regimes;and, it is the loss of this layer that facilitates further matrixfailure leading to collagen based tissue damage. Should damage to thecollagen progress without effective repair, it will serve as a lesionsite irritant impeding natural reconstitution of the amorphous boundarylubrication layer and lead to further tissue overload matrix failurethrough additional loading of a damaged and poorly structuredbiomechanical site. Because this layer has been noted to reform afterperturbation removal, its reconstitution, along with the favorablebiomechanical environment of damaged tissue removal that stimulates moreappropriate mechanotransductive biosynthetic gene expression, validatesthe approach of early intervention designed as a tissue rescue byremoving an irritant and allowing cellular and matrix component repairto manifest relative to perturbation specificity.

According to one embodiment of the present invention tissue water is atherapeutic target for electromagnetic force. Non-ablation tissuetreatment allows therapeutic regimens to be formulated at tissue surfaceand subsurface levels independently, but which may nonetheless beinterrelated. Physiochemical loading of tissue surfaces as a treatmentplatform is a complex discipline because it requires an understanding oftissue biology in both the native and diseased state. Variousphysiochemical loading regimens can be created based upontissue-specific therapeutic goals by modification, according to one ormore methods described herein, of the reactants and products availablein the primary reaction zone. Because the physiochemical loading oftissue surfaces is geographically or anatomically decoupled fromsubsurface tissue, non-ionizing electromagnetic forces at and belowtissue surfaces are enabled and particularly useful for an earlyintervention strategy since subsurface tissue in this settingdemonstrates retained cellular viability and a differentiated functionalphenotype. Electromagnetic fields facilitate charge flow throughaccelerated transfer rates and changing valence configurations and havebeen associated with increased enzymatic reaction efficiency, DNAstimulated biosynthesis, superficial extracellular matrix volumecontraction, cellular cytoprotection, and other domain specific geneexpression modulation.

In biologic tissue, water remains a substrate for non-ionizingelectromagnetic forces. The water acts as a facilitator of chargetransfer because of its mobility around hydrogen bonds. However, themechanisms by which electron transfer (often associated with redoxchemistry) interacts with proton transfer (often associated withacid-base phenomena) in the presence of charged macromolecular tissueconstituents that depend upon water to organize tertiary and quaternarystructure and bond interactions are not fully defined. Therefore,non-ionizing electromagnetic field induced changes in biologic tissuerequires in most instances further characterization of a tissue'sspecific elements within the native and diseased state available fortargeted manipulation.

Safe stabilization of articular cartilage lesion is an important earlysurgical intervention advance toward mitigating articular cartilagedisease burden. According to a system and method of an embodiment of thepresent invention, short-term chondrocyte viability andchondrosupportive matrix modification have been demonstrated withintissue contiguous to targeted removal of damaged articular cartilage.Surface chondrocyte responses within contiguous tissue after lesionstabilization according to an embodiment of the present invention isdescribed. Non-ablation radiofrequency lesion stabilization of humancartilage explants obtained during knee replacement was performed forsurface fibrillation. Time-dependent chondrocyte viability, nuclearmorphology and cell distribution, and the temporal response kinetics ofmatrix and chaperone gene transcription indicative of differentiatedchondrocyte function were evaluated in samples at intervals to 96 hourspost-treatment. Subadjacent surface articular cartilage chondrocytesdemonstrated continued viability for 96 hours post-treatment, a lack ofincreased nuclear fragmentation or condensation, persistent nucleic acidproduction during incubation reflecting cellular assembly behavior, anda transcriptional up-regulation of matrix and chaperone genes indicativeof retained biosynthetic differentiated cell function. This outcomeprovides evidence of treatment efficacy and suggest that the applicationof the non-ionizing electromagnetic forces impact cellular function topromote recruiting local chondrocytes to aid lesion recovery.

According to one embodiment of the present invention, non-ablationtreatment of diseased tissue enables targeting of diseased tissue byutilizing a protected electrode architecture for example thearchitecture described in U.S. Pat. Nos. 7,445,619 and 7,771,422. Thedevice tips inhibits electrode-to-tissue contact so that the resistivetissue heating and tissue electrolysis induced by current delivery intotissue and associated with tissue necrosis do not occur like in thermaland plasma radiofrequency ablation devices. The protective housingcreates a primary reaction zone that is shielded from the large physicalfluid-flow and convective forces present during surgical applicationenabling deployment of low-level radiofrequency energy delivery intointerfacing media rather than into tissue to create physiochemicalconversions that can be used for surgical work.

By manipulating active electrode current density dispersion, arepetitive molecular energy conversion loop under non-ionizingelectromagnetic forces is created wherein the rapid splitting andreconstitution of the water molecule occurs. Similar to the technologyutilized in a fuel cell that harnesses energy from the molecular bondsof water, these physiochemical conversions create products that areconcentrated through techniques such as capacitive deionization andconcentration enrichment and delivered to tissue surfaces throughselective throttling by the protective housing in a controlled andlocalized fashion through precipitation, sedimentation, thermal, orchemical gradient forces via redox magnetohydrodynamic fluid flow.

Diseased tissue is preferentially more sensitive to this physiochemicalloading as compared to non-diseased tissue, allowing for selectivemodification and preconditioning toward a state amenable to safe andeffective gentle mechanical débridement with the edge of the protectivehousing through augmented and naturally facile tissue cleavage planesinherent in articular cartilage. Non-ablation treatment of diseasedtissue or tissue in need of treatment is a matrix-failure-basedintervention that does not rely upon an electrode-to-tissue interface.The treatment physiochemically loads tissue surfaces in a manner thatcannot be accomplished with the exposed electrodes of thermal and plasmaradiofrequency ablation devices because of the induced internal cellulardamage they create.

This physiochemical loading is uniquely suited to affect the accessibleand degenerate surface matrix structure of damaged articular cartilagetissue preferentially rather than the intact chondron and matrix tissuedeep to the surface lesion level. As an illustration, pH shifts can begenerated, such as preferential sodium hypochlorite precipitation akinto production through neutrophil myeloperoxidase catalysis, andconfigured to react oxidatively with a wide variety of biomolecules attissue surfaces including the exposed proteoglycan aggregates of damagedarticular cartilage. Such pH shifts have been shown to producemechanical alterations at articular cartilage surfaces throughelectro-chemo-mechanical coupling via site-specific hydrogen anddisulfide bond alterations within constituent proteoglycan and collagen.These targeted pH gradients at tissue surfaces modulate mechanical andelectrochemical tissue matrix properties by altering fixed and variablecharge densities while affecting consequent extracellularintra-fibrillar hydration and osmotic character. This physiochemicalloading of accessible surface-based diseased tissue can alter therelative ratio of tension-compression non-linearity toward a stateamenable to gentle shear deformation mechanical débridement of tissuealready characterized by the deteriorating surface-layered shearproperties of collagen fibril disruption and orientation changes, weakcollagen-to-proteoglycan bonds, proteoglycan depletion, aberrant watercontent, and decreased fixed charge density.

Optimizing the surface shear properties of early articular cartilagedamage through cleavage plane stabilization is an important parameterfor overall lesion stabilization relative to perturbation specificity.These mechanisms do not impair residual chondrocyte viability. Theselayered surface properties exploited for cleavage plane shearstabilization have been observed in other tissue types and localesrequiring shear mitigation during surface degeneration and normallyrepresent a back-up mechanism to boundary lubrication regime failuresassociated with perturbation exceeding homeostasis and tissue repair forreversible lesions.

It has been demonstrated previously that non-ablation technologyselectively targets diseased tissue for removal without causing necrosisin contiguous healthy cartilage tissue while producing thechondrosupportive matrix modification of increased live chondron densityin the Superficial Zone. Since chondrocyte viability in subadjacenttissue is not altered, the opportunity presents to evaluate chondrocytebehavior in response to lesion stabilization after treatment with oneembodiment of the present invention. Notwithstanding the symptomaticimprovement obtained from articular cartilage lesion stabilization,eliminating the mechanical and biologic joint burden, non-ablationtechnology begins to serve the larger disease burden represented bydamaged articular cartilage.

The focal effects upon residual articular cartilage surface chondrocytesduring lesion stabilization with non-ablation technology wasexperimentally examined by evaluating time-dependent chondrocyteviability, nuclear morphology and cell distribution, and the temporalresponse kinetics of matrix and chaperone gene transcription indicativeof differentiated chondrocyte function.

Examples

As described herein, osteochondral specimens were harvested frompatients undergoing total knee replacement under an approvedInstitutional Review Board protocol. The total knee replacementprocedures were performed by a single surgeon in the normal course ofhis practice. The tissue to be normally discarded during the procedurewas examined prior to harvest once the knee joint was entered surgicallyto determine if it met study inclusion requirements. Specimens wereincluded that demonstrated an area of uniform partial thickness surfacefibrillation of sufficient size from which matched-pair test samplescould be obtained from each specimen. Specimens were divided intosmaller test sample parts after harvest by sharp sectioning and wereimmediately transferred to an ex vivo saline arthroscopic treatmentsetting.

A non-ablation radiofrequency device designed for cartilage lesionstabilization was used per manufacturer's specifications (Ceruleau®;NuOrtho Surgical, Inc.; Fall River, Mass.). Lesion stabilization wasperformed by one surgeon accustomed to radiofrequency device use. Thegoal of the procedure was to remove the fibrillated cartilage damage andsmooth the articular surface as determined by visual and tactile cues.Standard saline arthroscopic fluid was deployed at 20° C. with afluid-flow rate of 30 cc/min±5 cc/min which created consistent fluiddynamics in the set-up typical of in vivo arthroscopy. Energy delivery(Valleylab Force FX™-C; Covidien, Inc.; Mansfield, Mass.) wasstandardized at 25 W with a 8500 V peak-to-peak setting (4250 peakvoltage) and 390 kHz damped sinusoid bursts with a repetition frequencyof 30 kHz into 500 ohms (i.e. COAG, fulgurate).

Lesion stabilization treatment time was 5 seconds for all specimens witha technique of moving the probe tip tangentially across the tissuesurface with a consistent application pressure and speed as judged bythe surgeon to mimic in vivo treatment conditions. The protectivehousing edge was used to gently shear-debride the fibrillated tissueconcurrent with energy delivery for the allotted treatment time.Treatment did not deploy the heat delivery capabilities of non-ablationtechnology available through electrosurgical plenum positioning orincreased energy levels that can be used for the more demanding lesionstabilization associated with less fibrillated tissue displaying adifferent degeneration-based collagen fibril-to-water structure. Fortreatment described herein the delivery of heat to tissue surfaces islimited by a triphasic nature to low temperature changes (i.e. Δ0-7° C.)of interfacing media which is design-appropriate for the low thermalrequirements that would be necessary to manipulate exposed surface typeII collagen which begins to denature at 39° C. Paired sample explantsserved to generate untreated samples to serve as control that remainedin an identical treatment bath during the procedure.

After treatment, the untreated and treated samples were randomly dividedinto three groups for evaluation of time-dependent chondrocyteviability, nuclear morphology and cell distribution, and the temporalkinetics of versican, COL2A1, and HSPA1A gene expression in surfacechondrocytes.

The samples allocated to this group were evaluated at 1 hour and 96 hourintervals post-treatment for alterations in chondrocyte viability.Samples were prepared by thin sectioning to isolate the surface regioncontaining Superficial and Transitional Zone chondrocytes and matrixfrom the remainder of the tissue (sample dimensions: 3 mm thick by 7 mmsquare). These surface cartilage specimens were left as bulk tissue andincubated at 37° C. in Dulbecco's Modified Eagle's Medium (Invitrogen,Inc.; Carlsbad, Calif.) with fetal bovine serum and 1%penicillin-streptomycin (10,000 units and 10,000 μg, respectively). Noequilibration period was used and the specimens were incubated in 95%air with 5% CO₂. At 1 hour and 96 hours, three 0.5 mm coronal sectionsof each sample referencing the center of the untreated and treated siteswere created and prepared for staining by washing in HEPES bufferedsaline solution. Live/Dead® Reduced Biohazard Cell Viability Kit#L-7013, (Invitrogen, Inc.; Carlsbad, Calif.) was used permanufacturer's specification to stain samples. Samples weregluteraldehyde fixed, transferred to standard flat glass slides, andflooded with VectaShield® fluorescence protection oil prior to theplacement of #1.5 borosilicate glass cover slips over each samplesection.

Confocal fluorescence laser microscopy analysis was performed bypersonnel blinded to the identity of the treatment groups for eachsample. Confocal imaging was performed with an IX-81 inverted microscopecoupled to a FV300 confocal laser scanning unit (Olympus, Inc.; CenterValley, Pa.) using continuous wave 488 nm laser excitation (Sapphire488HP; Coherent, Inc.; Santa Clara, Calif.). Live cells were capturedunder the green fluoresce channel (505-525 nm) and dead cells werecaptured under the red fluoresce channel (577-634 nm), generating a Liveimage, a Dead image, and an Integrated image. Histologic characteristicsand cell viability between untreated and treated samples were assessedby comparative image evaluation for change in live and dead cellpopulations.

The samples allocated to this group were evaluated at the 1 hourpost-treatment interval to determine alterations in nuclear morphologyand cell distribution. Samples were maintained after treatment in thearthroscopic saline bath and prepared by thin sectioning as above. Three0.5 mm coronal sections of each sample referencing the center of thetreatment site and control were created and prepared for staining bywashing in HEPES buffered saline solution. Hoechst 33342 stain,trihydrochloride FluoroPure™ (#H-21492; Invitrogen, Inc.; Carlsbad,Calif.) was used per manufacturer's specification to stain samples.Samples were fixed and prepared for imaging as above.

Two-photon excitation microscopy was performed with an IX-81 invertedmicroscope coupled to a FV300 confocal laser scanning unit (Olympus,Inc.; Center Valley, Pa.) using a ×60, 1.2 NA water immersion objective(UPLSAPO 60XW; Olympus, Inc.; Center Valley, Pa.) for imaging. Adichroic mirror that reflected the near-infrared laser excitation lightand transmitted the visible (˜460 nm) bis-benzimide emission was used asthe excitation dichroic. The excitation source was a mode-lockedtitanium sapphire laser (Broadband Mai Tai; Spectra Physics, Newport,Inc.; Irvine. Calif.) operating at 800 nm with a pulse width of ˜100 fsand a pulse repetition rate of 80 MHz. An average power of ˜30 mW(measured at the back aperture of the microscope objective) was used toexcite the sample emission. A short pass filter with a cutoff wavelengthof 680 nm (FF01-680/SP; Semrock, Inc.; Rochester, N.Y.) was used tofilter residual 800 nm excitation laser light from the emission. Waterwas used as an immersion fluid to optically couple the sample andobjective to the cover slip.

Serial x-y plane tomographic images along the z-axis were generated toevaluate nuclear morphology and cell distribution. Dye exclusionproperties were not evaluated. These images were compressed into asingle x-y image brining the nuclear contents along the z-axis imageplanes into a single composite view to facilitate additionalinter-chondrocyte nuclear comparisons. BioView open sourcecross-platform application software (Center for Bio-Image Informatics,University of California; Santa Barbara, Calif.) was used to evaluatecell distribution patterns since all sample chondrocyte nuclei stainwith bis-benzimide. Axis rotations were performed to evaluate matrixmodifications of treated versus untreated samples that may affect celldistribution patterns as noted previously.

The samples allocated to this group were prepared by thin sectioning(sample dimensions: 2 mm thick by 5 mm square) and incubated as above.Untreated and treated samples were randomly assigned to incubationintervals of 1, 24, 48, 72, and 96 hours. At the end of each incubationinterval, the samples were frozen in liquid nitrogen and stored at −80°C. prior to RT-PCR testing. At testing, the samples were thawed andmechanically homogenized in lysis reagent (QIAzol #79306; Qiagen, Inc.;Valencia, Calif.). The homogenate was separated into aqueous and organicphases by centrifugation; and, mRNA was subsequently isolated by spincolumn elution (RNeasy Lipid Tissue Mini Kit #74804; Qiagen, Inc.;Valencia, Calif.).

Quantitative reverse transcriptase RT-PCR was performed (7300 Real-TimePCR System; Applied Biosystems, Inc.; Carlsbad, Calif.) by monitoringthe increase in reporter fluorescence of Taqman® gene expression assays(Applied Biosystems, Inc.; Carlsbad, Calif.) for versican(#Hs00171642_m1), COL2A1 (#Hs00264051_m1), and HSPA1A (#Hs00359163_s1).RNA concentration obtained was determined for both untreated and treatedsamples and evaluated for significant differences; sample purity wasevaluated for each specimen by determining R_(260/280) values(ultraviolet absorbance ratio at 260 nm and 280 nm). Expression changeswere quantified by the comparative C_(T) method to calculate relativefold changes normalized against 18s rRNA, calculated as the difference(ΔC_(T)) between the C_(T) value of the target and 18s rRNA control.Each sample was assayed in duplicate with relative expression calculatedand tabulated as 2^(−ΔΔCT) relative to each incubation interval samplegroup. The mean and standard deviation were calculated for each foldchange grouping. Curve fit regression analysis for mRNA expressiontemporal kinetic fold change was performed (TableCurve 2D, version5.01.02; Systat Software, Inc.; Chicago, Ill.) for the treated samplegroups compared to the average ΔC_(T) of the 1 hour untreated samplegroup serving as control and as time zero designed to demonstrate therelative scale of expression responses over time.

Four samples were allocated to this group; two untreated and twotreated. The untreated samples demonstrated surface fibrillationconsistent with gross visual inspection of the tissue at the time ofharvest. The Superficial Zone was disrupted by the fibrillation, butchondron appearance typical of this zone remained present in and aroundthe fibrillation. Live cells were abundantly observed with onlyoccasional dead cells residing in extruded positions at the frayedmargins of the fibrillated tissue. Treated samples displayed eliminationof the fibrillated tissue and smooth surfaces at the treatment site. Noevidence of necrotic tissue was present with the surfaces subadjacent tothe removed damaged tissue retaining Superficial Zone characteristicstypical of the intact Superficial Zone regions of the untreated samples.An increase in dead cell populations was not evident in either the 1hour or the 96 hour treated samples over the untreated sample groups;nor was a decrease in chondrocyte viability observed relative toincubation time. FIG. 1 depicts a representative post-treatmentintegrated Live/Dead cell viability stain section image demonstratingsurface characteristics and viable chondrocytes without evidence ofnecrosis or altered cellular viability. Note the lack of deadchondrocytes and a smooth surface in the tissue subadjacent to thetargeted removal of surface fibrillated tissue damage. Originalmagnification 10×.

Four samples were allocated to this group; two untreated and twotreated. The serial tomographic images demonstrated no evidence ofaltered nuclear morphology when compared to untreated samples. Asdepicted in FIG. 2, nuclear fragmentation or condensation (i.e.peripheral segregation or aggregation of chromatin into dense areasalong the nuclear membrane) were not present within the tissuechondrocytes subadjacent to the tissue targeted for removal, reflectingno evidence of chondrocyte apoptosis. Note the similar stainingintensities and lack of nuclear fragmentation or condensation. [Originalmagnification 60× water.] Cells typically contained a large nucleus withloosely packed euchromatin and little more dense heterochromatin.Homogeneous staining intensities appeared uniform in the z-axiscompressed images. Occasional single randomly positioned cellsdemonstrated altered nuclear morphologies in some samples which couldnot be linked to the treatment site and likely representedfixation-dependent or other causes typical within articular cartilage.FIG. 3A-C depicts a representative BioView images of cell distributionviewed from the x-y, x-z, and y-z vantage points. FIG. 3 (A) depicts thex-y plot; (B), the x-z plot; and (C), the y-z plot. Solid, dotted, anddashed lines with arrows reflect coordinate orientation between theimages displayed. Axis rotation assessments indicated evidence ofqualitative extracellular matrix contraction in the tissue immediatelycontiguous to the tissue targeted for removal and within the SuperficialZone region when compared to untreated samples.

Twenty samples were allocated to this group generating two untreated andtreated paired sample explants for each incubation interval for thepatient. The RNA quantity obtained included an untreated groupconcentration of 29.8±9.3 ng/μL and a treated group concentration of29.7±8.6 ng/μL, with no statistical differences between groups. Asdepicted in FIG. 4, R_(260/280) values were 1.76±0.06 and 1.76±0.10 foruntreated and treated samples, respectively, with no statisticalsignificance between groups at each time period during the incubation.Note the stability of RNA sample purity produced during the testingperiod for each incubation interval.

FIG. 5 depicts the fold change temporal kinetics of mRNA veriscan(CSPG2), COL2A1, and HSPA1A mRNA expression. Data reflects fold changerelative to the untreated samples at each incubation interval. Theuntreated sample group continued to express a stable mRNA level duringincubation and did not demonstrate significant fold change variationsduring the incubation period in any of the mRNAs examined. The treatedsample group demonstrated a large fold increase in expression earlyfollowed by a reversion to baseline expression comparable to untreatedsamples. Versican mRNA (CSPG2) was undetectable at 96 hours in thetreated samples and its standard deviation at the 24 hour incubationinterval was large.

FIG. 6 depicts curve regression fit of the expression events based onconcentration kinetic changes modeled as single production versus singleremoval rates. Note that the high statistical fit reflects a biologicphenomenon of damped exponential activation and deactivation/reactionexhaustion. Inset depicts an enlarged view of the modeled temporalexpression kinetics post-treatment. Data reflects treated sample groupscompared to the average ΔC_(T) of the 1 hour untreated sample groupserving as control and as time zero. The curve regression fit wasstatistically significant with strong relevance for versican (R²=0.72;p<0.04), COL2A1 (R²=0.92; p<0.0004), and HSPA1A (R²=0.83; p<0.002),demonstrating a scaled temporal response similar to the fold changeassessment based upon the control of each incubation interval.

Early post-treatment chondrocyte viability is not effected within tissuecontiguous to the treatment site during non-ablation radiofrequencylesion stabilization. Subadjacent surface articular cartilagechondrocytes treated as disclosed herein demonstrated one or more of thefollowing: continued viability for 96 hours post-treatment, a lack ofincreased nuclear fragmentation or condensation, persistent nucleic acidproduction during incubation reflecting cellular assembly behavior, anda transcriptional up-regulation of matrix and chaperone genes indicativeof retained biosynthetic differentiated cell function.

These activities support the efficacy of early surgical intervention;namely, to safely eliminate the irritant of damaged tissue withoutiatrogenic injury to contiguous tissue, to stabilize the remaininghealthy tissue through chondrosupportive matrix modifications, and toinduce an appropriate in situ biosynthetic cellular response within thetissue subadjacent to the lesion that retains differentiated function.While removing the irritant of damaged tissue may slow lesionprogression and permit local homeostatic and repair responses to occurless encumbered, the results of this study suggest that it is possibleto manipulate or induce cellular function thereby recruiting localchondrocytes to aid lesion recovery. Early surgical intervention can beviewed as a tissue rescue. Articular cartilage will continue to displaybiologic responses appropriate to its function, rather than convertingto a tissue ultimately governed by the degenerative material propertyresponses of matrix failure. If so, early intervention would impact thelate changes and disease burden of damaged articular cartilage.

Versican mRNA expression was evaluated in this study because it istranslated into a chondroitin sulfate proteoglycan that resides asaggregates within the inter-territorial matrix at articular surfaces.This site specificity reflects its functional role in the SuperficialZone extracellular matrix structure and therefore influencesmatrix-failure based lesion stabilization of early cartilage damage. Theversican proteoglycan displays low chondroitin sulfate density andsulfation levels, a property reflected in the fixed charge densityinherent in surface cartilage amenable to modification by physiochemicalloading during non-ablation treatment. Since surface damaged articularcartilage displays an altered fixed charge density due to layeredproteoglycan depletion, this exposed and accessible charge density is animportant therapeutic target during the surface events of lesionstabilization. Further, the normal charge barrier associated with theamorphous layer above the lamina splendens is functionally abolished indamaged articular cartilage surfaces.

Boundary lubrication regimes at normal articular cartilage surfacesprovide a unique charge density barrier due to surface activephospholipids which is remarkably resistant to the physiochemicalloading deployed during lesion stabilization particularly at sitesbathed in sodium chloride as during arthroscopy. This charge densityserves as a physiochemical loading barrier to and an intrinsic marginduring the surface events of lesion stabilization at intact surfaces. Itis a barrier which is robust enough to require enzymatic digestion,trauma, or other means like ablation energy to transgress in order toreach a collagen layer. The transient Versican mRNA transcriptionalup-regulation noted in response to lesion stabilization is consistentwith prior studies demonstrating post-treatment Superficial Zonephenotype characteristics and may be important in the reconstitution ofcartilage surface properties by chondrocytes after removal of thedamaged tissue irritant.

More intriguing, however, is that various isoforms of versican have beenimplicated in actions related to chondrogenesis through mesenchymalcondensation, cell aggregation, chondroprogenitor cell promotion, andchondrocyte gene expression. The adult isoform core protein size doesnot seem to change with osteoarthritis. There is evidence forSuperficial Zone progenitor cell populations and chondrocyteproliferation and clustering in early and fibrillated cartilage damage.Versican's mRNA post-translational role during early tissue responses tolesion stabilization may relate to a protective, and possiblytransitional, matrix construct during tissue assembly repair events bymodulating chondrocyte adhesion, morphology, proliferation,differentiation, or migration similar to its function noted duringrepair and self-assembly events in other tissue types.

The COL2A1 gene encodes the α-1 chain of type II collagen, the majorcollagen constituent of articular cartilage matrix and a good marker ofan activated functional phenotype. The transcriptional enhancement ofCOL2A1 after targeted lesion stabilization demonstrated in this studyserves as an assessment of the generalized chondrocyte function topromote articular cartilage-specific matrix synthesis. Chondrocytes atthe site of lesion stabilization retain the ability to produce mRNAreflective of their differentiated phenotype and characteristic ofmature cartilage. This indicates that the responses are not limited to afibroblastic-like dedifferentiation and low matrix gene expressionreflective of the phenotypic alterations of diseased tissue or othercartilage interventions during which chondrocytes continue to expresssynthetic activity post-treatment.

HSPA1A codes for highly conserved non-steric molecular chaperones thatparticipate in protein stabilization and assembly by mediating foldingand transport of existing or newly translated proteins. Chaperoneslevels are modulated to reflect the status of protein foldingrequirements within the cell such as preventing newly synthesizedproteins and assembled subunits from aggregation into non-functionalstructures that can occur due to natural macromolecular crowding.Chaperone levels reflect cellular requirements related to biosyntheticresponses as a means to monitor changes in cell environment. Inchondrocytes, HSPA1A proteins induce chondro-protection againstapoptosis and help resist the extracellular matrix destruction ofosteoarthritis. HSPA1A is constituently expressed in chondrocytes whileits inducible expression has been related to the terminaldifferentiation of chondrocytes and is increased in osteoarthritis as anearly marker. Although it is presently uncertain if the translationalproducts of versican and COL2A1 are routine protein clients of HSPA1Achaperones within human articular chondrocytes, HSPA1A expression inthis study is consistent with the temporal expression kinetics similarto other studies that have linked HSPA1A up-regulation with activematrix production and the reconstruction of chondrons.

It is possible that removal of damaged tissue itself can enablebiosynthetic activity in vivo as an unburdened homeostatic or repairresponse. By removing a biologic and mechanical irritant, the lesionsite can be altered to a more favorable perturbation-specificmechanotransductive environment supportive of differentiated geneexpression. However, since the tissue in this study was incubated in anunloaded state not reflective of physiologic perturbation specificity,it remains unclear whether the removal of the damaged tissue itself is asignaling mechanism responsible for the increased biosynthetic activityobserved. Although the untreated group reflected responses of surfacefibrillated articular cartilage incubated in an unloaded environmentwithout significant alteration in baseline mRNA expression studied, thetreated samples reflected differentiated biosynthetic functionconsistent with normal physiologic responses. The signaling mechanismsfor these responses are unlikely directly related to the physiochemicalloading of the cartilage surfaces utilized during lesion stabilization.

For instance, because the physiochemical loading deployed in this studydid not include heat delivery, HSPA1A induction should not be related toa temperature stress as up-regulation in chondrocytes does not occuruntil temperatures exceed 39° C.; a temperature that, interestingly, isconsistent with which exposed but normal extracellular matrix type IIcollagen begins to denature and that can be deployed in a controlledmanner by non-ablation technology for more demanding lesions. Further,and although extracellular pH changes can effect chondrocyte metabolismin culture, chondrocytes are not subjected to extracellular alterationsin pH during short-term topical loading in sodium chloride environments.Since non-ionizing electromagnetic forces are generated by non-ablationdevices to promote therapeutic biologic responses in tissuesunencumbered by necrosis-inducing current deposition, these forcesshould be considered a plausible induction mechanism at least partlyresponsible for the biosynthetic temporal response kinetics observed inthe treated samples.

For example, tissue temperature and pH are effected by non-ionizingelectromagnetic field voltage potentials that can generate local changesin biochemical reaction rates and protein conformation through orientingdipole moments above thermal noise, as well as, stimulate cartilageextracellular matrix production through voltage activated H⁺ channelsaltering intracellular pH. Such fields influence ion transporters thatregulate cell function, proliferation, differentiation, and migration,and when applied to cartilage have been shown to be chondroprotective,to reduce lesion progression, and to increase chondrocyte proliferation,lacuna formation, gene expression, protein synthesis, and extracellularmatrix production. Electromagnetic forces demonstrate activity atindependent gene initiation promoter domains through signaling pathwaysthat enable short exposures to induce rapid DNA activation; a mechanismlinking protein synthesis to electron charge transport accelerationinduced by electromagnetic forces.

Early intervention for articular cartilage damage remains an attractiveapproach to decrease disease burden because it is this setting thatretains the elements in situ for normal cartilage homeostasis andrepair. Chondrocyte behavior in culture provide important insight intoconcepts for in situ cartilage treatment. Maintaining chondrocytes intheir normal in vivo position preserves their interactions with theirextracellular matrix which are important when examining chondrocytebehavior. The cartilage samples described in the examples were incubatedin bulk. At a minimum, the results demonstrate that the chondrocyteswithin tissue contiguous to the site of targeted lesion stabilizationremain viable and are able to express genes appropriate todifferentiated chondrocyte function suggestive of tissue repair. Inaddition, these results demonstrate a small window into the coordinatedsequence of a healing event cascade that may be harnessed for furtherlesion repair and recovery.

Although cartilage has been historically described as a tissue type witha low expectant regenerative potential, the portion of this lowregenerative potential that is due to the biologic and mechanicalirritant of damaged cartilage is currently unknown. Non-ablationtechnology allows for the opportunity to evaluate the role that theirritant plays in this low expectant regenerative potential. Whereas thehallmarks of non-reversible articular cartilage lesions are moreobvious, the characteristics of self-repair and regeneration atreversible lesion sites and those relative to salvageable lesions arenot. Despite the heterogeneity of articular cartilage lesions,chondrocyte viability and a differentiated and healing phenotype at thesite of safe damaged tissue removal remain inextricably related to thereversibility of early lesions. Removal of this irritant relative toperturbation specificity is necessary to provide a more favorableenvironment to express mechanotransductive genes for biosynthesis; and,further, for targeted in situ manipulation of those genes. Even moreexciting is the potential to allow boundary lubrication regimes that aredepleted with damage to reconstitute over a non-irritated site viaself-assembly that may ultimately become a regional substrate for cellhoming techniques reflective of homeostasis and repair.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

Note that in the specification and claims, “about” or “approximately”means within twenty percent (20%) of the numerical amount cited.

Although the invention has been described in detail with particularreference to these preferred embodiments, other embodiments can achievethe same results. Variations and modifications of the present inventionwill be obvious to those skilled in the art and it is intended to coverin the appended claims all such modifications and equivalents. Theentire disclosures of all references, applications, patents, andpublications cited above are hereby incorporated by reference.

What is claimed is:
 1. A method for treating targeted tissue comprising:localizing an alternating current circuit device tip having electrodesin a conductive solution containing electroactive species in which atargeted tissue of a host is found; deploying current to the alternatingcurrent circuit device tip located in close proximity to the targetedtissue wherein the device tip inhibits electrode-to-tissue contact butpermits a shielded reaction zone for the conductive solution to reactwith at least one electrode of the alternating current circuit devicetip; moving an electron between electrodes of the alternating currentcircuit device tip utilizing an electron donor and acceptor carrierwithin the conductive solution containing electroactive species;producing an electromagnetic field quanta near the targeted tissue whenthe device tip is placed next to the targeted tissue and producing anelectron donor and an electron acceptor carrier associated with acharged specie intermediary created in the conductive solution formedabove a baseline dissociation rate; moving the charged specieintermediary created in the conductive solution toward the targetedtissue surface; and inducing an effect upon the targeted tissue or theconductive solution that is configured to treat the targeted tissue. 2.The method of claim 1 wherein the effect is produced by inducing geneexpression with energy that is not injury inducing to the targetedtissue.
 3. The method of claim 1 wherein the effect is produced byinducing superficial extracellular matrix volume contraction.
 4. Themethod of claim 1 wherein the effect is precision resection of thetargeted tissue.
 5. The method of claim 4 wherein the precisionresection of the targeted tissue is produced by denaturing an exposedproteoglycan aggregate of a damaged articular cartilage of the targetedtissue using the charged specie intermediary created in the conductivesolution having an induced pH below an isoelectric point of targetedtissue.
 6. The method of claim 5 wherein the exposed proteoglycan is achondroitin sulfate proteoglycan that resides as aggregates within aninter-territorial matrix at an articular surface.
 7. The method of claim1 wherein the effect is stirring of the conductive solution.
 8. Themethod of claim 7 wherein the stirring is microfluidic mixing of theconductive solution.
 9. The method of claim 1 wherein the charged specieintermediary created in the conductive solution comprise protons. 10.The method of claim 1 wherein the effect is directing the chargedspecies intermediary created in the conductive solution toward thetarget tissue.
 11. The method of claim 1 wherein the effect is apharmaceutical agent delivery to the target tissue.
 12. The method ofclaim 1 wherein the effect is an extracellular matrix modification. 13.The method of claim 1 wherein the effect is to upregulate a chondrocyteproliferation.
 14. The method of claim 1 wherein the effect is a genetranscription initiation.
 15. The method of claim 14 wherein the gene isindicative of a differentiated chondrocyte function.
 16. The method ofclaim 15 wherein the chondrocyte is a surface chondrocyte from thetarget tissue.
 17. The method of claim 14 wherein the gene is selectedfrom Versican, COL2A1 and HSPA1A.
 18. The method of claim 1 whereinmoving the charged specie intermediary created in the conductivesolution toward the targeted tissue surface is directionalized with aplenum.
 19. The method of claim 18 wherein the plenum has openingsthrough which the charged specie intermediary created in the conductivesolution are thrust.